Method for determination of onset risk of glaucoma

ABSTRACT

A method of determining the presence or the absence of a glaucoma risk, including the steps of detecting in vitro an allele and/or a genotype of a single nucleotide polymorphism which is located on a 31st base of a base sequence, in a sample from a subject, wherein the base sequence is at least one base sequence selected from the group consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto (step A), and comparing the allele and/or the genotype detected in the step A with at least one of an allele and/or a genotype, containing a high-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 514 (step B). According to the method of the present invention, the level of an onset risk of glaucoma in a sample donor can be determined by analyzing an allele or a genotype of a single nucleotide polymorphism in the present invention on the sample, so that the sample donor can take a preventive measure of glaucoma, or can receive appropriate treatments, on the basis of this risk.

TECHNICAL FIELD

The present invention relates to a method of detecting the presence of asingle nucleotide polymorphism associated with the onset of glaucoma, ora single nucleotide polymorphism with a high onset risk of glaucoma, anda kit used in the detection method.

BACKGROUND ART

Glaucoma is a disease which causes a characteristic optic nerve cuppingand an impairment in a visual field by retinal ganglion cell death.

An elevation in an intraocular pressure is considered to be a majorcause for the nerve cupping and the impairment in the visual field inglaucoma. On the other hand, there is also glaucoma in which anintraocular pressure is held within a normal range in statisticalcalculation, and even in this case, it is considered that glaucomadevelops because the intraocular pressure is at a sufficiently highlevel for causing the impairment in a visual field for an individual.

The basic treatment for glaucoma is to maintain an intraocular pressureat a low level, and it is necessary to consider the causes for a highintraocular pressure in order to maintain a low intraocular pressure.Therefore, in the diagnosis of glaucoma, it is important to classify thetypes of glaucoma in accordance with the levels of intraocular pressuresand causes therefor. As the causes for an elevation in an intraocularpressure, the presence or absence of closure of angle which is a majordrainage pathway for an aqueous humor filling an eye is important. Fromthese viewpoints, the primary glaucoma is roughly classified into thetwo groups of closed-angle glaucoma accompanying angle closure andopen-angle glaucoma without accompanying angle closure. Among them, theopen-angle glaucoma is classified into open-angle glaucoma, in a narrowsense, accompanying an elevation in an intraocular pressure, i.e.primary open-angle glaucoma, and normal tension glaucoma in which anintraocular pressure is held within a normal range.

It is known from old times that glaucoma is associated with inheritance.It is reported that 5 to 50% of individuals with open-angle glaucomahave a family history, and it is generally understood that 20 to 25% ofindividuals have hereditary causes. Based on these reports, studies on asearch for a gene responsible for glaucoma are performed. As a result,it is reported that a mutation in myocilin (MYOC) gene is associatedwith open-angle glaucoma (See Patent Publication: 1), and that amutation in optineurin gene (OPTN) is associated with normal tensionglaucoma (See

Non-Patent Publication: 1). However, all the genetic causes of glaucomacannot be explained only by these genes, and the presence of unknownglaucoma-related genes is expected.

On the other hand, a single nucleotide polymorphism means that asubstitution mutation in which a single base is changed into anotherbase is found in base sequences of the genome of an individual, and themutation exists in a certain frequency, generally a frequency of about1% or more, in the population of an organism species. A singlenucleotide polymorphism exists at intron or exon on genes, or any of theregions of the genome other than these.

Patent Publication 1: Japanese Patent-Laid Open No. 2000-306165 NonPatent Publication 1: Rezaie T and eleven others, Science, 2002,295(5557), 1077-1079.

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

Generally, an intraocular pressure or an ocular fundus photograph isused as a simple examination for glaucoma; however, these examinationsdo not necessarily lead to a definite diagnosis for glaucoma. Usually,in addition to these, visual field examinations are performed; however,there are some disadvantages that the examination is carried out for along period of time, causing burdens on patients, and that one must beaccustomed to the examination, so that initial examination results havelow reliability.

On the other hand, as mentioned above, the involvement of hereditarycauses is strongly suspected in the onset of glaucoma, but criticalresponsible genes are not identified. On the other hand, even if theinvolvement of a single gene to the disease cannot be explained by amutation or polymorphism, it is considered that there are numerousmutations or polymorphisms of a gene of which involvement to glaucoma isrelatively moderate, and the involvement of hereditary causes to theonset of glaucoma can be explained by a combined action of each of thesemutations or polymorphisms.

The inventors have remarked on a polymorphism on the genome, especiallya single nucleotide polymorphism, in order to find a gene associatedwith glaucoma.

By finding polymorphisms involved in the onset of glaucoma, a personhaving the polymorphisms which are found in a high frequency in glaucomapatients is predicted to have a high onset risk of glaucoma in futureeven before the onset thereof. Also, the polymorphisms can be applied toscreening of whether or not a visual field examination is required, inan early stage of glaucoma which is difficult to be detected by thesimple determination of glaucoma, i.e. a method such as a measurement ofintraocular pressure or an ocular fundus photograph, which is availableto be diagnosed only by carrying out the visual field examination. Inother words, a sample donor can take a preventive measure for the onsetof glaucoma by knowing the onset risk of glaucoma, and in addition, anecessary measure for preventing visual constriction such as a definitediagnosis and an initiation of treatment at an early stage according toa precision examination can be taken; therefore, it is important to finda polymorphism involved in the onset of glaucoma.

An object of the present invention is to provide a method of detecting asingle nucleotide polymorphism involved in the onset of glaucoma,thereby predicting an onset risk of glaucoma, and a kit used in thedetection method.

Means to Solve the Problems

The present inventors have found a single nucleotide polymorphismassociated with the onset of glaucoma by a comprehensive analysis ofknown polymorphic sites existing on the genome (autosome) in glaucomapatients and non-patients without a family history of glaucoma, andfurther found an allele identified in a high frequency in glaucomapatients and an opposite allele thereof, and a genotype identified in ahigh frequency in glaucoma patients, which is a combination of each ofthe alleles, in the single nucleotide polymorphism. Furthermore, thepresent inventors have found that a determination on whether or not asample donor is a person who is more likely to suffer from the onset ofglaucoma can be made at an even higher precision by performing thedetermination in a combination of these plural single nucleotidepolymorphisms associated with the onset of glaucoma. Thus, the presentinvention has been perfected thereby.

Concretely, the present invention relates to:

[1] a method of determining the presence or the absence of a glaucomarisk, including the steps of:

detecting in vitro an allele and/or a genotype of a single nucleotidepolymorphism which is located on a 31st base of a base sequence, in asample from a subject, wherein the base sequence is at least one basesequence selected from the group consisting of base sequences shown inSEQ ID NOs: 203 to 514 or a complementary sequence thereto (step A), and

comparing the allele and/or the genotype detected in the step A with atleast one of an allele and/or a genotype, containing a high-risk allele,in the base sequences shown in SEQ ID NOs: 203 to 514 (step B),

-   wherein the presence of a glaucoma risk is determined in a case    where the allele detected in the step A is the high-risk allele, or-   wherein the presence of a glaucoma risk is determined in a case    where the genotype detected in the step A is a homozygote of the    genotype containing the high-risk allele or a heterozygote when the    high-risk allele complies with a dominant genetic model, or-   wherein the presence of a glaucoma risk is determined in a case    where the genotype detected in the step A is a homozygote of the    genotype containing the high-risk allele when the high-risk allele    complies with a recessive genetic model;    [2] a method of determining the presence or the absence of a    glaucoma risk, including the steps of:

detecting in vitro, in a sample from a subject, an allele and/or agenotype of a single nucleotide polymorphism which is located on a 31stbase of a base sequence in a nucleic acid molecule, wherein the nucleicacid molecule comprises at least one base sequence selected from thegroup consisting of base sequences shown in SEQ ID NOs: 203 to 514 or acomplementary sequence thereto (step C1), or

detecting in vitro, in a sample from a subject, an allele and/or agenotype of a single nucleotide polymorphism, using a nucleic acidmolecule comprising a base sequence containing at least one basesequence selected from the group consisting of base sequences shown inSEQ ID NOs: 515 to 694 or a complementary sequence thereto (step C2),and

comparing the allele and/or the genotype detected in the step C1 or C2with at least one nucleic acid molecule comprising an allele and/or agenotype, containing a high-risk allele, in the base sequences shown inthe SEQ ID NOs: 203 to 514 (step D),

-   wherein the presence of a glaucoma risk is determined in a case    where the allele detected in the step C1 or C2 is the high-risk    allele, or-   wherein the presence of a glaucoma risk is determined in a case    where the genotype detected in the step C1 or C2 is a homozygote of    the genotype containing the high-risk allele or a heterozygote when    the high-risk allele complies with a dominant genetic model, or-   wherein the presence of a glaucoma risk is determined in a case    where the genotype detected in the step C1 or C2 is a homozygote of    the genotype containing the high-risk allele when the high-risk    allele complies with a recessive genetic model;    [3] a kit of determining the presence or the absence of a glaucoma    risk, containing

a nucleic acid molecule comprising at least one base sequence selectedfrom the group consisting of base sequences shown in SEQ ID NOs: 203 to514 or a complementary sequence thereto, or a partial sequence thereof,wherein the nucleic acid molecule comprises a single nucleotidepolymorphism which is located on a 31st base of a base sequence, and/or

a nucleic acid molecule comprising a base sequence containing at leastone base sequence selected from the group consisting of base sequencesshown in SEQ ID NOs: 515 to 694 or a complementary sequence thereto,

-   wherein the kit is for use in detecting in vitro an allele and/or a    genotype of a single nucleotide polymorphism in a sample from a    subject;    [4] a method of determining the presence or the absence of a    glaucoma risk, including the following steps of:-   step (i): extracting a nucleic acid molecule from a sample from a    subject,-   step (ii): detecting an allele of a single nucleotide polymorphism    which is located on a 31st base of a base sequence, wherein the base    sequence is at least one base sequence selected from base sequences    shown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto,    for the nucleic acid molecule extracted in the step (i), and-   step (iii): determining the presence or the absence of a glaucoma    risk, based on the allele detected in the step (ii);    [5] use of a nucleic acid molecule for determining a glaucoma risk,    wherein the nucleic acid molecule comprises at least one base    sequence, the base sequence being a base sequence selected from the    group consisting of base sequences shown in SEQ ID NOs: 203 to 514    or a complementary sequence thereto, or a partial sequence thereof,    wherein the nucleic acid molecule comprises an allele and/or a    genotype of a single nucleotide polymorphism which is located on a    31st base of a base sequence;    [6] a method of diagnosing glaucoma, including the steps of:

detecting in vitro an allele and/or a genotype of a single nucleotidepolymorphism which is located on a 31st base of a base sequence, in asample from a subject, wherein the base sequence is at least one basesequence selected from the group consisting of base sequences shown inSEQ ID NOs: 203 to 514 or a complementary sequence thereto (step E), and

comparing the allele and/or the genotype detected in the step E with atleast one of an allele and/or a genotype, containing a high-risk allele,in the base sequences shown in SEQ ID NOs: 203 to 514 (step F), whereinthe subject is diagnosed as glaucoma in a case where the allele detectedin the step E is the high-risk allele, or

-   wherein the subject is diagnosed as glaucoma in a case where the    genotype detected in the step E is a homozygote of the genotype    containing the high-risk allele or a heterozygote when the high-risk    allele complies with a dominant genetic model, or-   wherein the subject is diagnosed as glaucoma in a case where the    genotype detected in the step E is a homozygote of the genotype    containing the high-risk allele when the high-risk allele complies    with a recessive genetic model; and    [7] a method of determining an onset risk of glaucoma, including the    following steps of:-   step (I): determining the presence or the absence of the onset risk    of glaucoma, with the method as defined in claim 3,-   step (II): determining that a further risk determination is needed,    in a case where the presence of the onset risk is determined in the    step (I) for any one of single nucleotide polymorphisms, and-   step (III): further determining the presence or the absence of the    onset risk of glaucoma, with the method as defined in claim 5, in a    case of being determined that a further risk determination is needed    in the step (II).

Effects of the Invention

According to the method of the present invention, the presence or theabsence of the onset risk of glaucoma in a sample donor can bedetermined, and further the level of the risk can be predicted, byanalyzing an allele or a genotype of a single nucleotide polymorphism inthe present invention contained in a nucleic acid molecule derived fromthe genome existing in a sample. A sample donor can be provided with apreventive measure for glaucoma, or can receive appropriate treatments,on the basis of this risk. In addition, according to the method of thepresent invention, a sample donor who is suspected of glaucoma, havingan allele or a genotype containing a single nucleotide polymorphism inthe genome that is identified in a high frequency in glaucoma patients,can be given a detailed examination on whether or not the donor is withearly glaucoma, which is difficult to be determined sufficiently by anintraocular pressure or an ocular fundus photograph, and can be startedwith a treatment at an early stage in a case where the donor isdiagnosed as glaucoma.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is a method of determining the presence or theabsence of a glaucoma risk, including the step of detecting in vitro anallele and/or a genotype having at least one single nucleotidepolymorphism using at least one single nucleotide polymorphism(hereinafter may be referred to as SNP) contained in a base sequenceselected from the group consisting of specified base sequences or acomplementary sequence thereto, wherein the method of determining thepresence or the absence of a glaucoma risk further includes the step of:

comparing the allele and/or the genotype detected in the step with atleast one of an allele and/or a genotype, containing a high-risk allele,in the specified base sequences, in a sample from a subject,

-   wherein the presence of a glaucoma risk is determined in a case    where the detected allele is the high-risk allele, or-   wherein the presence of a glaucoma risk is determined in a case    where the detected genotype is a homozygote of the genotype    containing the high-risk allele or a heterozygote when the high-risk    allele complies with a dominant genetic model, or-   wherein the presence of a glaucoma risk is determined in a case    where the detected genotype is a homozygote of the genotype    containing the high-risk allele when the high-risk allele complies    with a recessive genetic model.

A great feature of the present invention resides in that a singlenucleotide polymorphism associated with the onset of glaucoma is found,further that in the single nucleotide polymorphism, an allele identifiedin a high frequency in glaucoma patients and an opposite allele thereof,and a genotype, which is a combination of each of the alleles identifiedin a high frequency in glaucoma patients are found, and used. Thepolymorphism as used herein refers to a matter that a diversity is foundin sequences of a specified location on the genome in a certain organismspecies, and a site at which the polymorphism exists (hereinafter alsoreferred to as polymorphic site) refers to a site on the genome that asingle nucleotide polymorphism is found.

In addition, the allele as used herein refers to each of types having adifferent base from each other that can be taken in a certainpolymorphic site. The genotype as used herein refers to a combination ofopposite alleles in a certain polymorphic site. Further, in a certainpolymorphic site, there are three types for a genotype which is acombination of opposite alleles, wherein a combination of the samealleles is referred to as a homozygote, and a combination of differentalleles is referred to as a heterozygote.

The opposite allele as used herein refers to another allelecorresponding to a specified allele among the alleles constituting acertain single nucleotide polymorphism.

In the present invention, the single nucleotide polymorphism associatedwith glaucoma refers to a single nucleotide polymorphism associated withthe onset of glaucoma or a single nucleotide polymorphism associatedwith the progression of glaucoma. In other words, the single nucleotidepolymorphism associated with the onset of glaucoma refers to a singlenucleotide polymorphism in which each allele or each genotype frequencyin the single nucleotide polymorphism significantly differs in astatistical analysis at a given p-value between glaucoma patients andnon-patients; and the single nucleotide polymorphism associated with theprogression of glaucoma refers to a single nucleotide polymorphism inwhich each allele or each genotype frequency in the single nucleotidepolymorphism significantly differs in a statistical analysis at a givenp-value between the progressive glaucoma cases and the nonprogressiveglaucoma cases.

In the present invention, the high-risk allele refers to an allelehaving a higher frequency in a glaucoma patient group than that of anon-patient group among each of the alleles of the single nucleotidepolymorphism associated with glaucoma. On the other hand, in the presentinvention, the low-risk allele refers to an allele opposite to thehigh-risk allele in a certain polymorphic site.

In addition, the homozygote and the heterozygote of a genotype aredefined in the same manner as in the high-risk allele and the low-riskallele.

In other words, in certain polymorphic sites, a combination of high-riskalleles or low-risk alleles themselves is referred to a homozygote, anda combination of a high-risk allele and a low-risk allele is referred toas a heterozygote.

An embodiment where allele frequencies of the glaucoma patient group andthe non-patient group are statistically compared is referred to as anallele model, and an embodiment where genotype frequencies thereof arecompared is referred to as a genotype model. There are a dominantgenetic model and a recessive genetic model in the genotype models,wherein the former means an embodiment where both a homozygote ofhigh-risk alleles and a heterozygote are involved with the onset risk,and the latter means an embodiment where a homozygote of a high-riskallele is involved with the onset risk.

In the present invention, the glaucoma risk refers to a risk concerningglaucoma. The onset risk of glaucoma refers to a possibility of thefuture onset of glaucoma determined by susceptibility to a disease. Inthe present invention, the prediction of a risk refers to adetermination of the presence or the absence of a future risk at thepresent stage, or determining the level of a future risk at the presentstage.

Also, the glaucoma as used herein means preferably open-angle glaucoma(OAG) or normal tension glaucoma (NTG), and the open-angle glaucoma,when used without specifying otherwise, means primary open-angleglaucoma (POAG) in a narrow sense, without embracing normal tensionglaucoma.

A method of identifying a single nucleotide polymorphism associated withglaucoma will be explained hereinbelow.

In the present invention, in selecting the single nucleotidepolymorphism associated with glaucoma, in particular, a candidate singlenucleotide polymorphism is selected by the steps including extracting atotal DNA from blood of each of glaucoma patients diagnosed as primaryopen-angle glaucoma or normal tension glaucoma and non-patientsdiagnosed as not being with glaucoma and determined to have no familyhistory of glaucoma according to a medical interview (also referred toas control individuals), and comparing allele or genotype frequencies ofindividual single nucleotide polymorphisms in the glaucoma patients andthe non-patients using known single nucleotide polymorphisms of about500,000 on the human genome as an index. Further, the allele or genotypefrequencies of individual single nucleotide polymorphisms for the singlenucleotide polymorphisms that are selected as candidates are obtainedfor glaucoma patients and non-patients that are different from thesample groups mentioned above. By combining these results, a singlenucleotide polymorphism of which difference in frequencies is recognizedwith high statistical significance is found. Here, a group composed ofthe glaucoma patients is referred to as a glaucoma patient group, and agroup composed of the non-patients is referred to as a non-patientgroup. By using the alleles or genotypes having a single nucleotidepolymorphism associated with the onset of glaucoma found according tothese analyses, the determination of the presence or the absence of theonset risk of glaucoma, and the prediction of the level of an onset riskcan be enabled. Although the details will be explained in the section ofExamples, a single nucleotide polymorphism associated with glaucomadisclosed in the present invention can be identified according to amethod given below.

(Identification of Single Nucleotide Polymorphism Associated withGlaucoma)

First, a total DNA is extracted from blood of each of patients diagnosedas glaucoma and non-patients determined to have no family history ofglaucoma. The total DNA in blood can be extracted by any known methods;for example, a DNA can be extracted by binding a DNA eluted by lysingcells to surfaces of magnetic beads coated with silica, and separatingand collecting the DNA utilizing a magnetic force.

The kind of a base in a single nucleotide polymorphism in the extractedDNA sample, i.e. an allele having a single nucleotide polymorphism canbe identified by any methods, including, for example, a method using animmobilized probe described later, or the like. Upon the identification,a probe used in the detection can be designed on the basis of thesequence information of a single nucleotide polymorphism of interest andsurrounding sequences thereof When the probe is designed, the sequenceinformation obtained from the database for known single nucleotidepolymorphisms such as dbSNP can be used as a reference. As to a probeused in the detection of a single nucleotide polymorphism, the detectioncan be made with either a probe complementary to a sense strand of thegenome, or a probe complementary to an antisense strand. Although thedetails will be described later, a kit in which probes capable ofdetecting single nucleotide polymorphisms existing on the human genomeare immobilized in large amounts, thereby making it possible todetermine alleles of numerous single nucleotide polymorphisms in asingle operation is commercially available, and whereby an allele in asample can be efficiently determined using the kit. Many of the kitsalso have the constitution that the alleles that are opposite to eachother contained in one sample are detected in a single operation, sothat a genotype can be determined.

The single nucleotide polymorphism associated with glaucoma can bedetermined by previously identifying an allele existing on DNA fromglaucoma patients and non-patients according to the method as mentionedabove, statistically comparing each of the allele frequencies and thegenotype frequencies in a glaucoma patient group against a non-patientgroup, and determining whether or not a difference that a p-value isbelow the significance level as defined by a given standard is caused inat least one of the allele frequencies and the genotype frequencies. Ina case where the difference is caused, the allele frequencies orgenotype frequencies for these factors in the glaucoma patient group andthe non-patient group are compared to determine whether any of thealleles or genotypes are identified in a high frequency in the glaucomapatient group.

In the statistical analysis, for example, a chi-square test can be used.Type I error caused by multiple comparisons can be corrected by a knowncorrection method, for example, Bonferroni method. In a case where acorrection is based on Bonferroni correction, for example, asignificance level can be obtained by dividing a p-value of 5×10⁻² bythe number of multiple comparisons, i.e. the number of polymorphisms tobe compared in the chi-square test. A single nucleotide polymorphismbelow the significance level determined in the manner described abovecan be selected as a more preferred single nucleotide polymorphism, anda method used in other known multiple corrections, for example, an FDRmethod or a permutation method may also be used in the selection of apreferred single nucleotide polymorphism. However, a known multiplecorrection method such as Bonferroni correction is a method presupposingthat the phenomenon of carrying out multiple analyses is completelyindependent; on the other hand, there are some cases where thephenomenon is not completely independent because linkage disequilibriumis found in a single nucleotide polymorphism as described later. Inother words, in the case as mentioned above, it is considered thatovercorrection takes place when correction is carried out according toBonferroni method. Especially, in the analysis of a single nucleotidepolymorphism over the whole genome as in the present invention, factorsto be statistically compared are highly enormous in number; therefore, ap-value serving as a standard is drastically lowered when multiplecorrections are performed, so that a possibility of an oversight of asingle nucleotide polymorphism associated with a disease becomes high(Schymick J C et al., Lancet Neurology. 2007: 6: 322-8; Van Steen K etal., Nature Genetics. 2005: 37: 683-691). An academically preferredmultiple correction method is not yet established, and as othercorrection methods, correction by another known correction method can becarried out, or a significance level can be set at any appropriatelevels within the range that would not be below the significance levelaccording to the Bonferroni correction. When any appropriate level isset, for example, the significance level in a case where about 500,000single nucleotide polymorphisms are analyzed repeatedly of 5×10⁻² isused, more preferably 1×10⁻², even more preferably 1×10⁻³, even morepreferably 1×10⁻⁴, even more preferably 3×10⁻⁵, and even more preferably1×10⁻⁵. As described later, the adjustment of the significance level asdescribed above is useful from the fact that it is confirmed that asingle nucleotide polymorphism identified to be associated with glaucomain the present invention exists continuously in a certain region on thegenome.

In addition, in general, it is known that type I error and thestatistical power are inversely proportional. A method of maintainingthe statistical power while lowering type I error includes a method ofperforming a single nucleotide polymorphism analysis in two dividedsteps (Skol A. D. et al., Nature Genetics. 2006: 38: 209-213). Forexample, in a case where a single nucleotide polymorphism analysis iscarried out for a fixed number of samples, firstly, analysis of enormoussingle nucleotide polymorphisms over the whole genome for a part ofsamples thereof is carried out as primary analysis, and secondly,analysis of single nucleotide polymorphisms narrowed down in the firstanalysis to some degree is carried out for the remainder samples assecondary analysis. In this case, in both of the analyses, a singlenucleotide polymorphism may be selected so as to have a relatively lowp-value, for example, 0.05; preferably, a single nucleotide polymorphismserving as a candidate in the first analysis may be selected at a givensignificance level, and the selected single nucleotide polymorphism maybe further analyzed using another sample. On the other hand, it is morepreferable that the results of the first analysis and the secondaryanalysis are not individually statistically analyzed but these resultsare combined and analyzed. In the case as mentioned above, the twoanalytical results can be combined by a known method of meta-analysis,for example, Mantel-Haenszel method (Mantel N et al., Journal of theNational Cancer Institute 1959: 22: 719-748). When the analyticalresults are combined according to a meta-analysis method such asMantel-Haenszel method, the significance level for the selection of asingle nucleotide polymorphism in individual analysis is not needed tobe at the level of Bonferroni correction, and the significance level maybe set by taking narrowing-down efficiency or the like intoconsideration. On the other hand, upon determination of whether or not asingle nucleotide polymorphism is significant by a p-value combined by ameta-analysis method such as Mantel-Haenszel method, it is preferable touse a significance level with considering multiple comparisons. Here,the Mantel-Haenszel method refers to a method of combining analyticalresults by weighting the results obtained by multiple analyses when achi-square test or the like is carried out. A statistical parametercombined by Mantel-Haenszel method includes, in addition to the p-value,an odds ratio described later or the like.

A single nucleotide polymorphism for the detection of the allele orgenotype associated with glaucoma is preferably a single nucleotidepolymorphism having a p-value of 1×10⁻³ or less, more preferably asingle nucleotide polymorphism having a p-value of 3×10⁻⁴ or less, evenmore preferably a single nucleotide polymorphism having a p-value of1×10⁻⁴ or less, and even more preferably a single nucleotidepolymorphism having a p-value of 3×10⁻⁵ or less, when the singlenucleotide polymorphism for the detection is based on the resultsobtained in a single analysis using, for example, a microarray in whichabout 500,000 single nucleotide polymorphisms are detected in a singleoperation. When the results are obtained by combining multipleanalytical results according to a meta-analysis method such asMantel-Haenszel method, the single nucleotide polymorphism for thedetection is preferably a single nucleotide polymorphism having ap-value of 1×10⁻² or less, more preferably a single nucleotidepolymorphism having a p-value of 3×10⁻³ or less, even more preferably asingle nucleotide polymorphism having a p-value of 1×10⁻⁴ or less, andeven more preferably a single nucleotide polymorphism having a p-valueof 3×10⁻⁴ or less.

It is preferable that a sufficient number of single nucleotidepolymorphisms are analyzed, in order to obtain highly reliable resultsupon analysis. For example, a polymorphic site having a lowdetermination rate of each single nucleotide polymorphism to the wholesample, i.e. a low call rate, is likely to have a high rate of typingerrors, so that the reliability is not high. Therefore, it is preferablethat the analysis is performed using a single nucleotide polymorphismhaving a sufficiently high call rate. As to the call rate that serves asa standard of accepting or rejecting a single nucleotide polymorphism,for example, it is preferable that a single nucleotide polymorphismshowing a call rate of preferably 70%, more preferably 75%, even morepreferably 80%, even more preferably 85%, and even more preferably 90%or more is employed.

Besides them, factors that can be considered upon analysis areHardy-Weinberg's equilibrium and minor allele frequency.

The Hardy-Weinberg's equilibrium means that a distribution frequency ofthe opposite alleles in a certain gene locus is constant even aftergenerations, in a genetically homogeneous population having a sufficientnumber of individuals formed by panmixia without a mutation or selectionpressure. Whether or not the Hardy-Weinberg's equilibrium is establishedcan be confirmed by some known methods, for example, a chi-square testand a direct probability calculation method of Fischer. In a populationof a sufficient number, it is considered that the Hardy-Weinberg'sequilibrium is established by a single panmixia, i.e. theHardy-Weinberg's equilibrium is established as long as inbreeding doesnot exist. Therefore, generally, under the assumption that the

Hardy-Weinberg's equilibrium is established in the general population,analysis of the Hardy-Weinberg's equilibrium is used for the purpose ofdetecting errors of genotype determination of a sample. However, even ifthe Hardy-Weinberg's equilibrium is established as a whole, when acertain genotype is unevenly distributed in a disease group or a controlgroup in a certain gene locus, for example, there are some cases where acertain genotype has a predominant influence on a disease, or the like;therefore, said analysis can be omitted, in a case where a search fordisease-associated genes is carried out.

The minor allele frequency refers to an allele frequency with a lowerfrequency of the frequencies of two alleles in a case where singlenucleotide polymorphisms are contained in two alleles. It is possiblethat a threshold thereof is arbitrarily set. As mentioned above, it ispreferable that a single nucleotide polymorphism having a minor allelefrequency of below 1% is rejected, because the concept of a singlenucleotide polymorphism is in that the single nucleotide polymorphismhas a minor allele frequency exceeding about 1%. On the other hand,there is a possibility that an allele having a very high or very lowallele frequency in a disease group has a predominant influence on adisease. It is considered that polymorphisms of which relativeinvolvement to a disease is relatively low are multiply involved insearch of polymorphisms causative of multi-factorial diseases;therefore, for the purpose of searching the polymorphisms as mentionedabove, an analysis excluding a frequency of a certain level or lower,for example, a minor allele of less than 5% can be a preferred means. Onthe other hand, in order to search polymorphisms that have predominantinfluences on a disease, it is effective not to reject the polymorphismsof the minor allele frequency.

From the allele or genotype associated with glaucoma thus obtained, theinformation such as a location on the genome at which a singlenucleotide polymorphism exists, the sequence information, a gene inwhich a single nucleotide polymorphism exists or a gene existing in theneighborhood, discrimination of intron or exon or a function thereof ina case where the single nucleotide polymorphism exists on the gene, anda homologous gene in other organism species can be obtained, byreferring to the database of known sequences such as GenBank, or thedatabase of known single nucleotide polymorphisms such as dbSNP, wherebya nucleic acid molecule used in the present invention is obtained, onthe basis of the information, and a probe or the like used in thepresent invention can be designed.

As the criteria for determining the presence or the absence of a risk ina single nucleotide polymorphism associated with glaucoma determined asmentioned above, a high-risk allele is defined. As mentioned above, inthe present invention, the high-risk allele refers to an allele having ahigher frequency in a glaucoma patient group than that of a non-patientgroup among each of the alleles of single nucleotide polymorphismsassociated with glaucoma, and in the present invention, the low-riskallele refers to an allele opposite to a high-risk allele in a certainpolymorphic site.

The determination of the presence or the absence of an onset risk can becarried out according to an allele or a genotype.

In a case where the determination is carried out according to an allele,the presence of the onset risk is determined for the single nucleotidepolymorphism because of having a high-risk allele.

In a case where the determination is carried out according to agenotype, the onset risk is determined by taking into considerationwhether the high-risk allele complies with a dominant genetic model, orwith a recessive genetic model. In a certain polymorphic site, when thefrequency of a homozygote of the high-risk allele and a heterozygote issignificantly high in a glaucoma patient group as compared to that of anon-patient group, it is said that these genotypes comply with adominant genetic model. The presence of an onset risk is determined forthe single nucleotide polymorphism in a case where the genotype is ahomozygote of the high-risk allele or a heterozygote, when the high-riskallele complies with a dominant genetic model. On the other hand, whenthe frequency of a homozygote of the high-risk allele is significantlyhigh in a glaucoma patient group as compared to that of a non-patientgroup, it is said that these genotypes comply with a recessive geneticmodel. The presence of an onset risk is determined for the singlenucleotide polymorphism in a case where the genotype is a homozygote ofthe high-risk allele, when the high-risk allele complies with arecessive genetic model.

The determination of the presence or the absence of an onset risk can bealso carried out according to a low-risk allele. As mentioned above, thelow-risk allele is an allele opposite to a high-risk allele, i.e. anallele identified in a high frequency in a non-patient group. In a casewhere the determination is carried out according to an allele, thepresence of an onset risk is determined for the single nucleotidepolymorphism because of not having a low-risk allele.

The same applies to a case of a genotype as well. When the determinationis carried out according to a genotype, an onset risk is determined bytaking into consideration whether the low-risk allele complies with adominant genetic model, or with a recessive genetic model. In a certainpolymorphic site, when the frequency of a homozygote of the low-riskallele and a heterozygote is significantly high in a non-patient groupas compared to that of a glaucoma patient group, it is said that thesegenotypes comply with a dominant genetic model. The presence of an onsetrisk is determined for the single nucleotide polymorphism in a casewhere the genotype is not a homozygote of the low-risk allele or aheterozygote, when the low-risk allele complies with a dominant geneticmodel. On the other hand, when the frequency of a homozygote of thelow-risk allele is significantly high in a non-patient group as comparedto that of a glaucoma patient group, it is said that these genotypescomply with a recessive genetic model. The presence of an onset risk isdetermined for the single nucleotide polymorphism in a case where thegenotype is not a homozygote of the low-risk allele, when the low-riskallele complies with a recessive genetic model.

As to whether the determination is carried out using a method for any ofan allele, a dominant genetic model, and a recessive genetic model, thesame method as in a method where a p-value judged to be significant isobtained can be used. In a case where the methods where a p-value judgedto be significant is obtained exist in a plurality for one singlenucleotide polymorphism, any of these methods may be used, andpreferably, the same method as in a method where the lowest p-value iscalculated is used.

Generally, in a single nucleotide polymorphism associated with adisease, a relative risk or an odds ratio is used as an index of anextent of the strength of the association that exists between one alleleor genotype and the presence or the absence of a disease.

Generally, the relative risk refers to a ratio of an incidence rate in agroup with a risk factor to an incidence rate in a group without a riskfactor. On the other hand, the odds ratio generally refers to a ratioobtained by dividing odds, which is a ratio of a proportion ofindividuals with a risk factor to a proportion of individuals without arisk factor in a patient group, by odds obtained in a non-patient groupin the same manner, which is in many cases used in a case-control studyas in the present invention. The odds ratio in the present invention isdetermined on the basis of the allele frequency or the genotypefrequency. In other words, the odds ratio of a single nucleotidepolymorphism associated with the onset refers to a value obtained bycalculating a quotient obtained in a ratio of an allele or genotypefrequency to another allele or genotype frequency in a glaucoma patientgroup, over a ratio of frequencies obtained in the same manner in anon-patient group. In the present invention, an extent to which an onsetrisk of glaucoma increases can be predicted by comparing a case ofhaving a certain allele or genotype to a case of having an allele orgenotype other than the above, using these indices. For example, when anodds ratio of a certain allele in a certain single nucleotidepolymorphism is greater than 1, the allele is an allele found in a highfrequency in a glaucoma patient group, in which the larger the oddsratio, the higher the onset risk of glaucoma for a sample donor havingthe allele. On the other hand, when an odds ratio of an allele is lessthan 1, the allele is an opposite allele of the allele that isidentified in a high frequency in a disease, in which the smaller theodds ratio, the lower the onset risk of glaucoma for a sample donorhaving the allele. The risk of a disease can also be predicted in thesame manner for a genotype.

In the present invention, the value of the odds ratio would be alwaysgreater than 1 by obtaining an odds ratio based on the high-risk allele.The risk prediction in a combination of plural single nucleotidepolymorphisms is facilitated by defining so that the odds ratio isgreater than 1 when having the high-risk allele as mentioned above.

Although the details are shown by the numerical formulas in the sectionof Examples, in a case where an odds ratio is obtained for an allele,the odds ratio may be a value obtained by calculating a quotientobtained in a ratio of the high-risk allele frequency to the low-riskallele frequency in a glaucoma patient group, over a ratio of thehigh-risk allele frequency to the low-risk allele frequency in anon-patient group. In order to obtain an odds ratio in a genotype, theodds ratio is obtained by taking into consideration whether thehigh-risk allele complies with a dominant genetic model, or with arecessive genetic model. In other words, a homozygote of the high-riskallele and a heterozygote becomes a risk factor when the high-riskallele complies with a dominant genetic model, and a homozygote of thehigh-risk allele becomes a risk factor when the high-risk allelecomplies with a recessive genetic model. Therefore, when the high-riskallele complies with a dominant genetic model, the odds ratio may beobtained by obtaining the sum of the homozygote frequency of thehigh-risk allele and the heterozygote frequency in a glaucoma patientgroup, and calculating a quotient obtained in a ratio of the above sumto the homozygote frequency of the low-risk allele, over a ratio offrequencies obtained in the same manner in a non-patient group. When thehigh-risk allele complies with a recessive genetic model, the odds ratiomay be obtained by obtaining the sum of the homozygote frequency of thelow-risk allele and the heterozygote frequency in a glaucoma patientgroup, and calculating a quotient obtained in a ratio of the homozygotefrequency of the high-risk allele to the above sum, over a ratio offrequencies obtained in the same manner in a non-patient group.

Further, the reliability of a single nucleotide polymorphism used in theprediction of a risk can be confirmed with an odds ratio. As mentionedabove, the meaning for the prediction of a risk reverses in a case wherethe odds ratio is 1 or more and a case where the odds ratio is 1 orless. Therefore, in a case where a calculated 95% confidence interval ofthe odds ratio includes 1, it cannot be said that the reliability forthe prediction of a risk for the odds ratio as mentioned above would behigh.

In addition, in a case where an onset risk of glaucoma is predicted by acombination of single nucleotide polymorphisms of the present invention,the level of the risk can be predicted by using the level of the oddsratio.

In the odds ratio according to an allele, the odds ratio of combined twoor more single nucleotide polymorphisms can be calculated according tothe following formula:

(RA1_(comb)RA2_(comb))/(RA3_(comb)RA⁴ _(comb))

wherein

-   RA1_(comb): an allele frequency in a case where at least one allele    is a high-risk allele in a glaucoma patient group;-   RA2_(comb): an allele frequency in a case where all the alleles are    low-risk alleles in the glaucoma patient group;-   RA3_(comb): an allele frequency corresponding to RA_(comb) in a    non-patient group; and

RA4_(comb): an allele frequency in a case where all the alleles arelow-risk alleles in the non-patient group.

For example, in a case where two single nucleotide polymorphismsassociated with the onset risk of glaucoma are combined, an odds isdetermined by dividing the frequencies in a glaucoma patient group allhaving high-risk alleles of a single nucleotide polymorphism, or havingany one of high-risk alleles, by the frequency in the glaucoma patientgroup not having any one of high-risk alleles. The odds ratio in a caseof a combination of the single nucleotide polymorphisms can bedetermined by calculating a ratio of said odds to the odds of that in anon-patient group obtained in the same manner.

In order to obtain an odds ratio according to a combination in cases ofgenotypes, the odds ratio is obtained by taking into considerationwhether the high-risk allele complies with a dominant genetic model, orwith a recessive genetic model, in the same manner as that alone.

In the odds ratio according to a dominant genetic model, the odds ratioof combined two or more single nucleotide polymorphisms can becalculated according to the following formula:

(RGd1_(comb)RGd2_(comb))/(RGd3_(comb)RGd4_(comb))

wherein

RGd1_(comb): a frequency at which at least one genotype is a homozygoteof a high-risk allele or a heterozygote, in a glaucoma patient group;

-   RGd2_(comb): a frequency at which all the genotypes are homozygotes    of a low-risk allele in the glaucoma patient group;-   RGd3_(comb): a frequency of the genotype corresponding to    RGd1_(comb) in a non-patient group; and-   RGd⁴ _(comb): a frequency at which all the genotypes are homozygotes    of a low-risk allele in the non-patient group.

For example, in a case where both the high-risk alleles of the twosingle nucleotide polymorphisms comply with a dominant genetic model,the odds ratio may be obtained by calculating a quotient obtained in aratio of the frequency at which any of the two single nucleotidepolymorphisms are a homozygote of a high-risk allele or a heterozygotein a glaucoma patient group to the frequency at which both the twosingle nucleotide polymorphisms are a homozygote of a low-risk allele inthe glaucoma patient group, over a ratio of frequencies of thoseobtained in the same manner in a non-patient group.

In the odds ratio according to a recessive genetic model, the odds ratioof combined two or more single nucleotide polymorphisms can becalculated according to the following formula:

(RGr1_(comb)RGr2_(comb))/(RGr3_(comb)RGr4_(comb))

wherein

-   RGr1_(comb): a frequency at which at least one genotype is a    homozygote of a high-risk allele, in a glaucoma patient group;-   RGr2_(comb): a frequency at which all the genotypes are homozygotes    of a low-risk allele in the glaucoma patient group;-   RGr3_(comb): a frequency of the genotype corresponding to    RGr1_(comb) in a non-patient group; and-   RGr4_(comb): a frequency at which all the genotypes are homozygotes    of a low-risk allele in the non-patient group.

For example, in a case where both the high-risk alleles of the twosingle nucleotide polymorphisms comply with a recessive genetic model,the odds ratio may be obtained by calculating a quotient obtained in aratio of the frequency at which any of the two single nucleotidepolymorphisms are a homozygote of a high-risk allele in a glaucomapatient group to the frequency at which both the two single nucleotidepolymorphisms are a homozygote of a low-risk allele in the glaucomapatient group, over a ratio of frequencies of those obtained in the samemanner in a non-patient group. Here, the odds ratio for a combination ofsingle nucleotide polymorphisms can also be calculated by combiningsingle nucleotide polymorphisms having different genetic forms.

Generally, the odds ratio increases by combining two or more singlenucleotide polymorphisms, as compared to a case where these singlenucleotide polymorphisms are used alone. Therefore, by a combination oftwo or more single nucleotide polymorphisms, a sample donor with ahigher onset risk of glaucoma would be identified, whereby theimprovement in the precision of the prediction can be made possible, ascompared to the case where a single nucleotide polymorphism is usedalone.

In order to confirm the improvement of the precision of the predictionof an onset risk of glaucoma according to a combination of singlenucleotide polymorphisms in the present invention, a multivariateanalysis can be employed. As the multivariate analysis method, a methodwell known to one of ordinary skill in the art such as logisticregression analysis method, discriminant analysis method, multiplelinear regression analysis method, or proportional hazard analysismethod can be employed, among which the logistic regression analysismethod is effective in a case where a dichotomous variable such as thepresence or the absence of an onset risk of glaucoma is handled.

The logistic regression analysis method refers to a method of analyzinga degree to which multiple independent variables (H) contribute in orderto describe a single dependent variable (Φ) (Wakariyasui Igaku Tokeigaku(Easy Medical Statistics), pp. 148-179, Toshio MORIZANE, MedicalTribune). By performing the logistic regression analysis, a regressioncoefficient (λ) for each independent variable can be obtained, and thisregression coefficient can be utilized as an index showing a degree towhich each independent variable describes a dependent variable. Inaddition, a dependent variable on each obtained independent variable canbe calculated by substituting this regression coefficient into thefollowing formula:

Φ=1/{1+exp[−(λ0+λ1Π1+λ2Π2+λ3Π3+ . . . )]}

Here, when the logistic regression analysis is performed, theindependent variables π used in analysis can be previously narrowed downusing a stepwise method or the like. The stepwise method refers to amethod for selecting independent variables Π so as to maximize theregression coefficients by adding an optional independent variable Π. Inother words, it means that after the regression coefficient is maximizedby adding an arbitrary independent variable Π, the same outcome isobtained even if another independent variable Π is further added.

In the present invention, by combining any two or more single nucleotidepolymorphisms determined to be involved in the onset of glaucoma, theextent to which the precision of the prediction of an onset risk isimproved can be known, as compared to that where each of the singlenucleotide polymorphisms is used alone. Concretely, the above formula isobtained according to logistic regression analysis by using each of anytwo or more single nucleotide polymorphisms as an independent variable Π(homozygote of one allele=0, heterozygote=1, homozygote of an oppositeallele=2). In each sample, a dependent variable Φ is calculated bysubstituting a variable for each single nucleotide polymorphism intothis formula. When a dependent variable Φ is greater than a giventhreshold (for example, 0.5), this sample donor is determined to be aglaucoma patient. The determination results are collated with the matterof whether the sample donor having a single nucleotide polymorphism wasactually the glaucoma patient. According to the combination of the twoor more single nucleotide polymorphisms in the present invention, animprovement in a concordance proportion is confirmed, whereby theprecision improvement by the combination can be confirmed.

In addition, the single nucleotide polymorphisms which exist ingenetically sufficiently close locations to each other are inherited inlinkage, not inherited independently, in some cases. In a certainpopulation, a state in which a linkage as described above is heldregardless of occurrence of a recombination by mating is referred to asa linkage disequilibrium, and a unit holding the linkage is referred toa haplotype block or an LD block.

In the experiment results by the present inventors, it is found that asingle nucleotide polymorphism associated with glaucoma actually mayexist in clusters in a relatively closely on the genome in some cases.It is considered that these regions belong to an LD block associatedwith glaucoma. In order to determine an LD block associated withglaucoma, the LD block can be determined by analyzing single nucleotidepolymorphisms which exist in the region as many as possible by themethod mentioned above, and applying an algorithm to determine an LDblock, for example, an EM algorithm. In addition, when the singlenucleotide polymorphism associated with glaucoma in the presentinvention belongs to a known LD block, the LD block can be considered asan LD block associated with glaucoma. Genome Browser provided on theinternet web sites by California University at Santa Cruz, or the likecan be consulted for a known LD block.

Because a single nucleotide polymorphism that belongs to an LD blockassociated with glaucoma is linked to a single nucleotide polymorphismassociated with glaucoma identified according to the experiments of thepresent inventors, it can be considered that the single nucleotidepolymorphism that belongs to an LD block associated with glaucoma alsoassociates with glaucoma in the same manner; therefore, the singlenucleotide polymorphism is used in the prediction of an onset risk orprogressive risk of glaucoma. In addition, by re-determining a sequencewithin the LD block associated with glaucoma, or a sequence surroundingthe single nucleotide polymorphism associated with glaucoma that isidentified according to the experiments by the present inventors, thereis a possibility that an unknown single nucleotide polymorphism which islinked with the single nucleotide polymorphism, in other words, which isassociated with the onset of glaucoma or the progression thereof, isfound. Whether or not the found single nucleotide polymorphism isactually associated with the onset of glaucoma or the progress thereofcan be determined by comparing an allele or genotype frequency of adisease group with that of a control group in the same manner asexplained above.

In the present invention, an intronic single nucleotide polymorphism(iSNP) refers to one in which a single nucleotide polymorphism isidentified in intron. A coding single nucleotide polymorphism (cSNP)refers to one that is accompanied by a change in an amino acid sequence,such as a codon in which the single nucleotide polymorphism is mutatedto a codon encoding other amino acids or a termination codon, amongthose in which single nucleotide polymorphisms exist in regionstranslated in a protein. A silent single nucleotide polymorphism (sSNP)refers to one without accompanying a change in an amino acid sequence,among those in which a single nucleotide polymorphism is identified in acoding region. A genomic single nucleotide polymorphism (gSNP) refers toone in which a single nucleotide polymorphism exists in a region notencoding the gene on the genome. A regulatory polymorphism (rSNP) refersto a single nucleotide polymorphism existing in a site that is thoughtto be involved in the transcriptional regulation.

As described above, a single nucleotide polymorphism may exist in anylocation on the genome, any cases of which can be associated with adisease. In a case where a single nucleotide polymorphism exists in theintron or a non-coding region, there may be some cases where the singlenucleotide polymorphism may influence a gene expression control, orsplicing that takes place after the gene transcription or stability ofmRNA. In a case where a single nucleotide polymorphism exists in thecoding region, by substitution of its base, a codon corresponding to acertain amino acid may be changed to a codon corresponding to adifferent amino acid, or may undergo a change, for example, a change toa termination codon, or the like, which may lead to a change in thestructure of a protein encoded thereby. Changes in expression levels orfunctions of genes by these changes consequently lead to changes inexpression levels or functions of proteins encoded by the genes, whichcan be causes for various diseases. In a case where the genomic singlenucleotide polymorphism is associated with a disease, there is apossibility that a region including the polymorphic site is actuallytranslated, and influences in some way to other gene expressions. In acase where a silent single nucleotide polymorphism is associated with adisease, it is considered that a different polymorphism associating withthe disease exists in the surrounding of the single nucleotidepolymorphism, and the polymorphism and the silent single nucleotidepolymorphism are linked, so that the association with the disease isfound. Similarly, in a single nucleotide polymorphism other than thesilent single nucleotide polymorphism, even when the single nucleotidepolymorphism itself is not a direct cause for glaucoma but links to apolymorphism which is the true cause for glaucoma existing in thesurrounding, the association of these single nucleotide polymorphismsand glaucoma may be found in some cases. In the case as described above,as described later, a polymorphism which is causative of glaucoma can befound by re-sequencing the surrounding of the single nucleotidepolymorphism in the present invention. However, in any case, thesesingle nucleotide polymorphisms can be also used for the purpose ofpredicting an onset risk of glaucoma, regardless of whether or not thesewould be the true causes for the disease.

(Nucleic Acid Molecule Comprising Allele Associated with Glaucoma)

In an embodiment of the present invention, there are provided a nucleicacid molecule comprising a single nucleotide polymorphism associatedwith glaucoma, and a nucleic acid molecule having a sequencecomplementary to the nucleic acid molecule comprising a singlenucleotide polymorphism associated with glaucoma.

The nucleic acid molecule comprising a single nucleotide polymorphismassociated with glaucoma or the nucleic acid molecule having a sequencecomplementary to the nucleic acid molecule can be used as a marker fordetermining the level of the onset risk of glaucoma. Further, thesenucleic acid molecules can be used as a probe for detecting an allele oran opposite allele thereof identified in a high frequency in glaucomapatients, or determining a genotype, in the single nucleotidepolymorphism. In addition, in a case where the single nucleotidepolymorphism exists on exon or in the neighborhood thereof, thesenucleic acid molecules can be used in the detection of transcripts ofgenes.

The nucleic acid molecule constituting the genome of an eukaryote isconstituted by double strands of a sense strand and an antisense strandcomplementary to the sense strand. In other words, the single nucleotidepolymorphism also exists on the sense strand and the antisense strand,and the nucleic acid molecule of the present invention embraces both ofthese strands because the detection of a single nucleotide polymorphismof both the strands is equally significant.

Nucleic acid molecules comprising any one of single nucleotidepolymorphisms listed in Tables 1 and 2, Tables 5 to 25, Tables 26 to 28and Tables 29 to 51 shown later, nucleic acid molecules comprising anysingle nucleotide polymorphisms existing in a region or on a genedetermined by the linkage disequilibrium data or the like listed inTables 3 and 4 shown later, and nucleic acid molecules complementary tothese nucleic acid molecules are all embraced in the nucleic acidmolecule of the present invention.

In an embodiment of the present invention, the nucleic acid molecule ofthe present invention is preferably nucleic acid molecules comprising asingle nucleotide polymorphism listed in Tables 1 and 2, Tables 26 to 28or Tables 52 to 62 shown later, or nucleic acid molecules complementarythereto, wherein

in a case where the single nucleotide polymorphism is gSNP, the nucleicacid molecule is a nucleic acid molecule comprising a sequence from anext base of a known single nucleotide polymorphism on an upstream sideof the sense strand to a base before a known single nucleotidepolymorphism on a downstream side, or a nucleic acid molecule comprisinga sequence complementary thereto,

in a case where the single nucleotide polymorphism is iSNP, sSNP orcSNP, the nucleic acid molecule is a nucleic acid molecule comprising afull length of the gene on the genome including the single nucleotidepolymorphism, a nucleic acid molecule comprising a sequencecomplementary thereto, and a nucleic acid molecule containing acomplementary DNA (cDNA) molecule comprising the single nucleotidepolymorphism or a sequence complementary thereto,

in a case where the single nucleotide polymorphism is rSNP, the nucleicacid molecule is a nucleic acid molecule comprising a sequence from anext base of a known single nucleotide polymorphism on an upstream sideof the sense strand to a full length of the gene existing downstream ofa promoter region in which the single nucleotide polymorphism exists, ora nucleic acid molecule comprising a sequence complementary thereto.

The nucleic acid molecule in the present invention is not limitedwhether it is a deoxyribonucleic acid, a ribonucleic acid, or a peptidenucleic acid, and a nucleic acid molecule comprising a mixed sequencethereof is also embraced in the present invention. In a case where aribonucleic acid is used in the nucleic acid molecule in the presentinvention, in the sequence of the nucleic acid molecule in the presentinvention (including a sequence complementary thereto), thymine may beread as uracil. In addition, these nucleic acid molecules may besubjected to chemical modifications as occasion demands, within therange that would not impair a function to be used in the presentinvention. In this case, the function refers to a function ofaccomplishing the purpose of using the nucleic acid molecule.

The nucleic acid molecule in the present invention can be synthesized bya known method, for example, a phosphoramidite method, on the basis ofthe sequence information disclosed herein, or the sequence informationobtained by searching the information disclosed herein with thedatabase. The nucleic acid molecule can be synthesized using acommercially available DNA synthesizer. In addition, the nucleic acidmolecule in the present invention can be obtained from a samplecomprising DNA from human according to a known method such as a PCRmethod, or in some nucleic acid molecules, can be obtained from a samplecontaining RNA from human according to a known method such as an RT-PCRmethod. As to primers that are necessary for the obtainment, one ofordinary skill in the art can design the primers on the basis of thesequence information disclosed herein, or the sequence information thatcan be searched from ID of the database disclosed herein. For example,in a case where a PCR method is used, primers having about 10 to about30 bases that have sequences homologous to a part of the sequences ofthe nucleic acid molecule of interest can be used, and in a case wherean RT-PCR method is used, the nucleic acid molecule can be obtained bycarrying out reverse transcription reaction using an oligo dT primer, ora random hexamer, or the like to prepare cDNA, and amplifying a sequenceof interest in the cDNA by the PCR method mentioned above.

The nucleic acid molecule has a length of preferably from 16 to 55bases, and more preferably from 23 to 27 bases or 47 to 53 bases. It ispreferable that the nucleic acid molecule is a nucleic acid moleculecontaining the polymorphic site mentioned above and a surroundingsequence thereof, or a sequence complementary thereto.

When a nucleic acid molecule comprising a single nucleotide polymorphismassociated with the onset of glaucoma is selected, in a case where thenucleic acid molecule is selected based on the results obtained in asingle analysis using a microarray in which, for example, 500,000nucleic acid molecules are detected in a single operation, the nucleicacid molecule in the present invention is preferably a nucleic acidmolecule having a p-value of 1×10⁻³ or less, more preferably a nucleicacid molecule having a p-value of 3×10⁻⁴ or less, even more preferably anucleic acid molecule having a p-value of 1×10⁻⁴ or less, and even morepreferably a nucleic acid molecule having a p-value of 3×10⁻⁵ or less.In a case where plural analytic results are combined and obtainedaccording to a method of meta-analysis, such as Mantel-Haenszel method,the nucleic acid molecule is preferably a nucleic acid molecule having ap-value of 1×10⁻² or less, more preferably a nucleic acid moleculehaving a p-value of 3×10⁻³ or less, even more preferably a nucleic acidmolecule having a p-value of 1×10⁻³ or less, even more preferably anucleic acid molecule having a p-value of 3×10⁻⁴ or less, and even morepreferably a nucleic acid molecule having a p-value of 1×10⁻⁴ or less.

As a different means of selecting a preferred nucleic acid molecule, asignificance level is set according to a known multiple correctionmethod, whereby a preferred nucleic acid molecule can be selected. In acase where a correction is based on Bonferroni correction, for example,a significance level can be obtained by dividing a p-value of 5×10⁻² bythe number of multiple comparisons, i.e. the number of polymorphisms tobe compared in the chi-square test. A nucleic acid molecule having asingle nucleotide polymorphism below the significance level thusobtained may be selected as a more preferred nucleic acid molecule. Uponthe selection, Bonferroni correction may be performed using a p-valuethat is combined according to a method of meta-analysis, such asMantel-Haenszel method, and the number of single nucleotidepolymorphisms to be subject for the meta-analysis. Other known methodsused in multiple corrections, for example, an FDR method or apermutation method may be used in the selection of a preferred nucleicacid molecule.

(Method of Detecting Single Nucleotide Polymorphism Associated withGlaucoma and Method of Predicting Onset Risk of Glaucoma)

Another embodiment of the present invention provides a method ofdetecting the presence or absence of an allele or genotype having a highfrequency in glaucoma patients in a sample containing a nucleic acidmolecule from the genome. The samples may be any ones so long as thenucleic acid molecules from the genome can be extracted, and forexample, blood, white blood cells, hair root, hair, saliva, oral mucosacells, skin, tissues such as muscles or organs obtained by biopsy, orthe like can be used.

As mentioned above, the nucleic acid molecule constituting the genome ofan eukaryote is constituted by a sense strand and an antisense strandthat are complementary to each other, and the determination of theallele of the single nucleotide polymorphism in the present inventioncan also be performed by detecting any one of the bases of the sensestrand and the antisense strand of the polymorphic site.

As mentioned above, in the method of determining the presence or theabsence of the allele or genotype in a sample containing a nucleic acidmolecule, any means can be used. For example, hybridization is carriedout using a probe specific to each of the alleles, preferably a probe inthe present invention described later, which is designed based on thesequence information disclosed in the present invention, and each of thealleles can be detected by detecting signals therefor. In addition, eachof the alleles opposite to each other, in other words, an allele havinga high association to a disease for a certain single nucleotidepolymorphism and an allele having a low association thereto are eachprovided with different labels, and a probe capable of hybridizing thesealleles to a polymorphic site, or an immobilized probe such as amicroarray in which each of alleles opposite to each other isimmobilized is used, whereby each of the alleles opposite to each othercontained in the same sample can be detected. In the constitution asdescribed above, not only the alleles of the sample, but also thegenotypes can be determined. In addition, in a case where an immobilizedprobe such as a microarray in which each of the alleles opposite to eachother is immobilized on the same carrier is used, a constitution thatthe hybridization is carried out in a single operation, and that thedetection is carried out in a single operation can be also taken.

As another method of detecting a single nucleotide polymorphism in thepresent invention, the following method can be utilized. Examples of amethod of hybridization using a probe are Taqman method, Invader(registered trademark) method, LightCycler method, cyclin probe method,MPSS method, beads-array method, and the like, and any of these methodscan be employed. As to the probe for detecting the same allele, a morepreferred probe may differ in some cases depending upon a method used inthe detection. The determination of the allele or genotype of the singlenucleotide polymorphism in the present invention does not depend uponthe detection method, and it is preferable to use a suitable probedepending upon the detection method.

The Taqman method is a method of detecting a genetic polymorphism usingan oligoprobe having a given length in which a fluorescent substance isbound to a 5′-side, and a quencher is bound to a 3′-side. The presenceor absence of the polymorphism is determined by hybridizing a probe to anucleic acid molecule having a polymorphism of interest, cutting off apart of the probe on the 5′-side by a PCR reaction, and measuring afluorescent amount emitted by a fluorescent substance.

The Invader method is a method of detecting a genetic polymorphism usinga probe (reporter) which has a sequence common to a 3′-side of a nucleicacid molecule having a polymorphism, but the sequence on a 5′-side beingcompletely different therefrom, and a probe (invader) having only asequence common to a 5′-side. The nucleic acid molecules of interest andthese two probes are hybridized, a product is then treated with anuclease, a part of the cut-out reporter probe is hybridized with aprobe for detection having a fluorescent substance and a quencher, ahybridization product is treated with a nuclease, and the fluorescentsubstance is released, whereby the presence or absence of thepolymorphism is determined by a fluorescent amount thereof.

The LightCycler method is a method of detecting a polymorphism includingthe step of hybridizing a polymorphic detection probe having afluorescent substance and an anchor probe having a quencher, to anucleic acid molecule having a polymorphism previously amplified by PCR.If the hybridized DNA is gradually heated, the polymorphic detectionprobe is released when a given temperature is reached, and the presenceor absence of the polymorphism is determined by measuring thisfluorescent amount.

The cyclin probe method is a polymorphic analysis method utilizing aprobe having a fluorescent substance or a quencher on each end of a DNA(DRD probe), wherein DNA sequences are bound in a manner that both endsof an RNA sequence having a sequence complementary to a polymorphic siteof a nucleic acid molecule of interest are sandwiched. A DRD probe ishybridized to a nucleic acid molecule of interest previously amplifiedby PCR or the like, RNase is allowed to act on this complex, and afluorescent dye is released, whereby the presence or absence of thepolymorphism is determined by measuring this fluorescent amount.

The MPSS method is a method of performing polymorphic analysis using anencoded adaptor probe and a decoder probe. The encoded adaptor probe isan oligo DNA having a 4-bases long protruding end on a 5′-side,subsequently a recognition sequence for a restriction enzyme BbvI, and asingle-stranded sequence bound to a decoder probe on a 3′-side. On theother hand, the decoder probe is a single-stranded oligo DNA having afluorescent substance on a 3′-side, and the decoder probe containing 4different sequences, each sequence specifically hybridizing to a singleencoded adaptor probe. The nucleic acid molecule having a polymorphismis previously immobilized on beads, and an initiation adaptor containinga recognition sequence for BbvI is bound thereto, to digest with BbvI toform a 4-bases long protruding end. The ligation with the encodedadaptor probe is carried out sequentially from a 3′-side of theprotruding 4 bases, and the sequence of the bound encoded adaptor isdetected with a specified decoder probe.

The beads array method is a method of performing the determination of agenotype including the step of combining beads to which a probe forallele detection and an oligonucleotide (address sequence) specifyingthe location information on the array of signals detected by the probefor allele detection are bound. For example, there are Golden Gate Assayusing beads immobilized with only an address sequence (23 bases) ofIllumina, and Infinium (registered trademark) Assay using beads in whichprobes (50 bases) for allele detection are bound to an address sequence(30 bases). In both the methods, which location on an array the probesfor allele detection are bound can be known for each of the beadsarranged arbitrarily on the array, on the basis of the address sequence.

The method of the Golden Gate Assay will be shown hereinbelow. In thedetection of a single nucleotide polymorphism, two kinds of probes(allele-specific probes) specifically hybridizing to each allele, and aprobe capable of specifically hybridizing to a sequence located 1 to 20bases downstream on the 3′-side of the single nucleotide polymorphism(downstream sequence recognition probe) are used. In the downstreamsequence recognition probe, an address sequence for specifying thelocation on the array is provided. In addition, these three probescontain a sequence to which universal primers described later are bound.The three probes are annealed with a genomic DNA, and a DNA polymeraseand a ligase are added thereto. By carrying out an extension reactionand a ligation reaction, an allele-specific product ligating a gapbetween the allele-specific probe and the downstream sequencerecognition probe is formed. A reaction for PCR is carried out with thisallele-specific product as a template using two kinds offluorescent-labeled universal primers, each being specific to eachallele, and a universal primer bound to the downstream sequencerecognition probe. A labeled PCR product is hybridized to anoligonucleotide immobilized on beads via an address sequence. Thefluorescence on the beads is detected with a confocal laser scanner,thereby determining an allele and a genotype.

The method of the Infinium Assay will be shown hereinbelow. An array byIllumina [Illumina, iSelect™ Genotyping BeadChip] described later is inaccordance with this method. There are two methods in the detection ofan allele by this array. In one method, two kinds of probes (probes forallele detection of 50 bases long, Infinium I type) only differing by abase at a 3′-end, wherein the 3′-end is a site for detecting a singlenucleotide polymorphism, are used. Whole genome amplification for agenomic DNA is previously carried out, and fragmentation with an enzymeis carried out. The probe and the fragmented genomic DNA are hybridized,and thereafter an allele-specific extension reaction takes place,whereby a base on the downstream (3′-side) by a single base of apolymorphic site labeled with a single kind of a fluorescent dye isincorporated corresponding to the probe. In another method, one kind ofprobe without having an allele-specific sequence of a single nucleotidepolymorphism in the probe is used (probe for allele detection of 50bases, Infinium II type). A 3′-end of this probe has a sequence up to asingle base upstream (5′-side) from a polymorphic site. The probe andthe fragmented genomic DNA are hybridized, and according to a singlebase extension reaction, a base labeled with either one of two kinds offluorescent dyes is incorporated corresponding to a single nucleotidepolymorphic site of interest. In both the methods, the fluorescence isdetected by a confocal laser scanner, thereby determining an allele anda genotype.

Here, the details of properties for length, modification and the like ofprobes used in the hybridization method mentioned above will bedescribed later.

In addition, a method without carrying out hybridization with a probeincludes PCR-RFLP method, SSCP method, mass spectrometry and directsequencing method.

The PCR-RFLP method is a method including the steps of forming differentDNA fragments according to enzymatic digestion of a nucleic acidmolecule having a polymorphism due to the existence of a polymorphism ina cleavage site of the restriction enzyme in the nucleic acid molecule,and determining the presence or absence of a polymorphism from adifference in electrophoretic patterns thereof. A nucleic acid moleculeof interest is amplified by PCR, this amplified fragment is cleaved witha restriction enzyme, and a fragment formed electrophoretically isanalyzed. The length of the nucleic acid molecule comprising anamplified polymorphism is usually from 50 to 10,000 base pairs, and morepreferably from 100 to 1,000 base pairs.

The SSCP method is a method including the steps of amplifying a nucleicacid molecule having a polymorphism by PCR, forming a single-strandedDNA, electrophoresing the product, and determining the presence orabsence of a polymorphism from a difference in the electrophoreticpatterns thereof. The nucleic acid molecule of interest is amplified byPCR, and a single-stranded DNA is formed by subjecting this amplifiedfragment to heat or an alkali treatment. This single-stranded DNA formsa base sequence-specific higher-order structure; therefore, if theseamplified fragments are electrophoresed, a difference in theelectrophoretic mobility is found due to the difference in itsstructure. The primer used in PCR is labeled with a radioisotope orfluorescent substance.

In addition, the length of the nucleic acid molecule comprising anamplified polymorphism is usually from 50 to 10,000 base pairs, and morepreferably from 100 to 1,000 base pairs.

The mass spectrometry is a method including the steps of ionizing apolymer with a matrix and a laser or the like, accelerating the ionizedpolymer in a high electric field to allow a flight to a detector, andidentifying mass from a difference in the flight time, or the like. Thismass spectrometry is combined with the above primer extension method orthe like to detect a polymorphism. Concretely, a single base extensionreaction is carried out with a primer complementary to a sequence up toa single base upstream of a polymorphic site of a nucleic acid moleculehaving a polymorphism, any one of 4 kinds of dideoxyribonucleotides, anddeoxyribonucleic acids other than those corresponding the above, and adifference in mass of nucleic acid products having different sequencesincorporated in a 3′-end is determined, whereby a polymorphism can beidentified.

The direct sequencing method is a method of directly reading off a basesequence of a nucleic acid molecule having a polymorphism.Representative methods are called Sanger method (dideoxy method). Aprimer that is unlabeled or labeled with a radioisotope or a fluorescentsubstance is bound to a nucleic acid molecule of interest, an extensionreaction with Klenow enzyme or the like is stopped with four kinds ofdideoxyribonucleotides that are unlabeled or labeled with a radioisotopeor a fluorescent substance, the product is digested with a restrictionenzyme, and a DNA fragment generated is separated by electrophoresis.The base sequence of a 3′-end is read off in the order of fragmentshaving a lower molecular weight on the basis of an electrophoreticimage, thereby a base sequence containing a few bases before and after apolymorphism is determined. As a modified method thereof, there is amethod called a primer extension method. This is a method including thesteps of carrying out a single base extension reaction using a primercomplementary to a sequence up to a single base upstream of apolymorphic site of a nucleic acid molecule having a polymorphism, andreading off any one of the sequences of the 4 kinds ofdideoxyribonucleotides incorporated in the 3-end. There are variousmethods in the identification of this dideoxyribonucleotides; forexample, 4 kinds of nucleotides are labeled with different fluorescentsubstances, and separated and identified electrophoretically. Inaddition, a method of converting pyrophosphoric acid formed during anextension reaction to ATP, and identifying its ATP from luminescence ofluciferase is also employed. The length of the primer used in theextension reaction is usually from 10 to 300 base pairs, and preferablyfrom 15 to 25 base pairs.

In the present invention, the hybridization means that a nucleic acidmolecule having a certain sequence is associated with a nucleic acidmolecule complementary to at least a part of the nucleic acid moleculevia a hydrogen bond on the basis of base sequences that arecomplementary to each other. The kind of the complementary nucleic acidmolecule associated with the original nucleic acid molecule may beidentical or different, and a nucleic acid constituting these nucleicacid molecules can be a deoxyribonucleic acid, a ribonucleic acid, or apeptide nucleic acid. In these nucleic acid molecules, when referred tothe ribonucleic acid, in the sequence of the nucleic acid molecule(including a complementary sequence), thymine may be read as uracil.

The stringent conditions in the present invention mean conditions inwhich a nucleic acid molecule having a sequence complementary to apartial sequence of a nucleic acid molecule having a certain sequence isspecifically hybridized to the nucleic acid molecule (Fred M. Ausuble etal., Current Protocols in Molecular Biology, 2.10.1-2.10.16, John Wileyand Sons, Inc). Concrete examples of the conditions as described aboveinclude conditions such as a temperature lower than a meltingtemperature (Tm) of a complex formed between a nucleic acid moleculehaving a certain sequence and a complementary nucleic acid moleculehybridized to the nucleic acid molecule by preferably from about 5° toabout 30° C., and by more preferably about 10° to about 25° C., areaction solution for hybridization, such as SSC (mixed solution ofsodium chloride and sodium citrate) in a concentration of 0.01 to6-folds, SSPE (mixed solution of sodium chloride, sodiumdihydrogenphosphate, and EDTA) or MES (a mixed solution of2-(N-morpholino)ethanesulfonic acid and tetramethylammonium chloride)buffer, and hydrogen ion concentrations of a pH of from 6 to 8. Forexample, the stringent conditions in a case where an immobilized probeis prepared by immobilizing a 25 by DNA probe include conditions ofhybridization at 49° C. in the MES buffer (hydrogen ion concentrationsbeing from 6.5 to 6.7) in a 1-fold concentration, and sequentiallywashing with SSC (hydrogen ion concentrations being 8.0) in a 6-foldconcentration at 25° C., and thereafter SSC (hydrogen ion concentrationsbeing 8.0) in a 0.6-fold concentration at 45° C.

In the present invention, the term allele-specific (or specific toallele) means that the allele is contained in a sequence from the genomeincluding the polymorphic site or in a prepared nucleic acid moleculeincluding the polymorphic site, or a certain nucleic acid molecule iscapable of specifically hybridizing under stringent conditions to anucleic acid molecule having a sequence containing the allele in thepolymorphic site, in other words, in the manner of being capable ofdiscriminating the allele and the opposite allele.

Base sequences of 61 bases in length including a single nucleotidepolymorphism associated with the onset of glaucoma, disclosed in thepresent invention, are composed of two pairs of base sequences whichdiffer only by a base in the center (i.e. 31st base) (i.e. those pairsare consisting of a sequence having odd number of SEQ ID No. and asequence having even number of SEQ ID No.), and the 31st base is apolymorphic site. The high-risk alleles in the polymorphic sites arelisted in Tables 1 and 2 or Tables 52 to 63 given later. In any of thesesingle nucleotide polymorphisms, in a case where the existence of anallele that exists in a high frequency in glaucoma patients isdetermined, a high-risk allele in a sample is detected, whereby theexistence of the allele that exists in a high frequency in glaucomapatients can be determined.

In addition, as to any single nucleotide polymorphisms associated withthe onset of glaucoma identified above, the genotype can be determinedby detecting the presence or the absence of each of the alleles oppositeto each other contained in one sample. In detail, in a case where only acertain allele is detected, the genotype is a homozygote of the allele,and in a case where two alleles are detected, the genotype is aheterozygote having the two alleles. In at least one of these singlenucleotide polymorphisms, by detecting a genotype, it is determinedwhether or not the genotype that is identified in a higher frequency ina glaucoma patient group than that of a non-patient group exists in asample. In other words, in the single nucleotide polymorphism mentionedabove, when the high-risk allele complies with a dominant genetic model,a homozygote of the high-risk allele or a heterozygote is a genotypethat is identified in a higher frequency in a glaucoma patient groupthan that of a non-patient group, and when the high-risk allele complieswith a recessive genetic model, a homozygote of the high-risk allele isa genotype that is identified in a higher frequency in a glaucomapatient group than that of a non-patient group. It is preferable thateach of the opposite alleles is measured in a single operation, from theviewpoint of reducing judgmental error.

The sample is analyzed in the manner described above, and in a casewhere the allele or genotype that is identified in a higher frequency ina glaucoma patient group than that of a non-patient group exists in thesample, there are some high probabilities that an individual donatingthe sample not having glaucoma at the present point is predicted to havea high onset risk of glaucoma, or is determined that a precisionexamination for glaucoma such as visual field examination is necessary,and that an individual donating the sample who is suspected of havingglaucoma should be diagnosed as glaucoma.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, the single nucleotide polymorphism used in thedetection is a single nucleotide polymorphism which is located on a 31stbase of a base sequence, wherein the base sequence is at least one basesequence selected from the group consisting of base sequences shown inSEQ ID NOs: 203 to 514 or a complementary sequence thereto, morepreferably a single nucleotide polymorphism which is located on a 31stbase of a base sequence, wherein the base sequence is at least one basesequence selected from the group consisting of base sequences shown in

SEQ ID NOs: 203 to 238 or a complementary sequence thereto, even morepreferably a single nucleotide polymorphism which is located on a 31stbase of a base sequence, wherein the base sequence is at least one basesequence selected from the group consisting of pairs of base sequencescontaining a single nucleotide polymorphism listed below or acomplementary sequence thereto, wherein, as mentioned above, in thepairs of SEQ ID NOs: shown in a to r, each of the pairs of sequencescorresponds to one single nucleotide polymorphism, and each of the basesequences is a base sequence containing an allele opposite to each otherof the single nucleotide polymorphism in a 31st base:

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238.

In a case where any one of the single nucleotide polymorphisms is used,especially, it is preferable that an allele of a single nucleotidepolymorphism located on a 31st base of a base sequence is used, whereinthe base sequence is at least one base sequence selected from the groupconsisting of the following base sequences containing a singlenucleotide polymorphism:

SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ IDNO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID NO: 219,SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO: 228, SEQ IDNO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235, and SEQ ID NO:238,

or a complementary sequence thereto.

Here, these sequences are sequences containing a high-risk allele ineach of polymorphic sites.

Further, the precision of the determination of a future onset risk ofglaucoma can be improved by detecting a combination of two or more ofalleles or genotypes associated with glaucoma in the present invention,using one sample.

For the single nucleotide polymorphisms to be combined, any ones can beused so long as they are a single nucleotide polymorphism in the presentinvention, preferably a single nucleotide polymorphism having a lowp-value, and more preferably a single nucleotide polymorphism of whichp-value obtained by combining the results obtained in two analyses by ameta-analysis method, such as Mantel-Haenszel method, is determined tobe significant even below the level of Bonferroni correction. Inaddition, from a different viewpoint, it is preferable to use a singlenucleotide polymorphism that is confirmed to contribute to theimprovement in the precision of the risk prediction by a combinationaccording to the logistic regression analysis described later. On theother hand, since the single nucleotide polymorphisms in a state oflinkage disequilibrium mentioned above show the same behavior, in a casewhere plural single nucleotide polymorphisms in a state of linkagedisequilibrium are combined, risks of glaucoma based on the same regionmay be evaluated unnecessarily seriously in some cases. In a case wherea risk of a disease is predicted by combining the single nucleotidepolymorphisms in the present invention, when it is intended to evaluateall the risks in even weighting, it is preferable that the prediction iscarried out employing only one of the single nucleotide polymorphisms inthe state of linkage disequilibrium, in a case that the plural singlenucleotide polymorphisms that are in the state of linkage disequilibriummentioned above are contained.

In a case where a risk is predicted according to a combination of anytwo or more single nucleotide polymorphisms in the present invention, anonset risk of glaucoma can be predicted using the regression formulaobtained by the logistic regression analysis. Concretely, the regressionformula according to the logistic regression analysis is obtained byrespectively using each of the any two or more single nucleotidepolymorphisms as an independent variable Π (homozygote of one allele=0,heterozygote=1, homozygote of an opposite allele=2). In each sample, adependent variable Φ is calculated by substituting a value correspondingto each single nucleotide polymorphism into this formula. When adependent variable Φ is greater than a given threshold (for example,0.5), the determination can be made that this sample donor has an onsetrisk.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, in a case where any two or more single nucleotidepolymorphisms are combined, the single nucleotide polymorphisms used inthe detection are preferably single nucleotide polymorphisms which arelocated on 31st bases of base sequences, wherein the base sequences arebase sequences containing two or more different single nucleotidepolymorphisms, selected from the group consisting of base sequencesshown in SEQ ID NOs: 203 to 514 or a complementary sequence thereto,

more preferably single nucleotide polymorphisms which are located on31st bases of base sequences, wherein the base sequences are basesequences containing two or more different single nucleotidepolymorphisms, selected from the group consisting of base sequencesshown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto,

even more preferably single nucleotide polymorphisms which are locatedon 31st bases of base sequences, wherein the base sequences are basesequences containing two or more different single nucleotidepolymorphisms, selected from the group consisting of pairs of basesequences containing a single nucleotide polymorphism listed below or acomplementary sequence thereto,

wherein, as mentioned above, in the pairs of SEQ ID NOs: shown in a tor, each of the pairs of sequences corresponds to one single nucleotidepolymorphism, and each of the base sequences is a base sequencecontaining an allele opposite to each other of the single nucleotidepolymorphism in a 31st base:

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   i: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and-   even more preferably single nucleotide polymorphisms which are    located on 31st bases of base sequences, wherein the base sequences    are base sequences containing 10 or more different single nucleotide    polymorphisms, selected from the group consisting of pairs of base    sequences containing a single nucleotide polymorphism listed above    or a complementary sequence thereto, and-   even more preferably single nucleotide polymorphisms which are    located on 31st bases of base sequences, wherein the base sequences    are base sequences containing all the different single nucleotide    polymorphisms, selected from the group consisting of pairs of base    sequences containing a single nucleotide polymorphism listed above    or a complementary sequence thereto.

In addition, it is preferable that the single nucleotide polymorphismsto be used in combination are those that are not in the state of linkagedisequilibrium, and from this viewpoint, in all the embodiments of thecombinations mentioned above, supposing that

-   a group composed of a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is a base sequence belonging to the group consisting of:-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   or a complementary sequence thereto, is named as a single nucleotide    polymorphism of Group 1,-   a group composed of a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is a base sequence belonging to the group consisting of:-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   or a complementary sequence thereto, is named as a single nucleotide    polymorphism of Group 2,-   a group composed of a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is a base sequence belonging to the group consisting of:-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   or a complementary sequence thereto, is named as a single nucleotide    polymorphism of Group 3,-   a group composed of a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is a base sequence belonging to the group consisting of:-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238,-   or a complementary sequence thereto, is named as a single nucleotide    polymorphism of Group 4,-   it is preferable to use-   any one of the single nucleotide polymorphisms in Group 1 in a case    that the single nucleotide polymorphisms belonging to Group 1 are    used,-   any one of the single nucleotide polymorphisms in Group 2 in a case    that the single nucleotide polymorphisms belonging to Group 2 are    used,-   any one of the single nucleotide polymorphisms in Group 3 in a case    that the single nucleotide polymorphisms belonging to Group 3 are    used, and/or-   any one of the single nucleotide polymorphisms in Group 4 in a case    that the single nucleotide polymorphisms belonging to Group 4 are    used.

Further, in all the embodiments of the combinations mentioned above, itis preferable that an allele of a single nucleotide polymorphism locatedon a 31st base of a base sequence is used, wherein the base sequence isa base sequence containing two or more different single nucleotidepolymorphisms, selected from the group consisting of the following basesequences containing a single nucleotide polymorphism:

-   SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ    ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID    NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO:    228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235,    and SEQ ID NO: 238,-   or a complementary sequence thereto.-   Here, these base sequences are sequences containing a high-risk    allele in each of polymorphic sites.

(Probe Capable of Detecting Allele Associated with Glaucoma)

In another embodiment of the present invention, an allele-specificnucleic acid molecule or probe (hereinafter referred to as probe)capable of detecting an allele associated with glaucoma, and a method ofdetecting an allele or a genotype associated with glaucoma using theprobe are provided.

Any probes may be used so long as the probe is capable of hybridizingunder the stringent conditions to an allele-specific sequence, in apolymorphic site of the single nucleotide polymorphism associated withglaucoma in the present invention. The determination of the allele in apolymorphic site can be made by detecting any one of polymorphic sitesof the sense strand and the antisense strand on the genome; therefore,the probe in the present invention embraces any one of sequencescomplementary to a sequence specific to an allele of the sense strandand sequences complementary to a sequence specific to an allele of theantisense strand, in other words, sequences specific to an allele of thesense strand. The probe in the present invention can also be used in thedetection of cDNA or mRNA, containing a single nucleotide polymorphismin the present invention. In a case where the probe is used in thedetection of cDNA or mRNA, a probe in which the single nucleotidepolymorphism exists in exon or neighborhood thereof is used.

The probes capable of detecting each of alleles of the single nucleotidepolymorphisms listed in Tables 1 and 2, Tables 5 to 25, Tables 26 to 28,Tables 29 to 51, or Tables 52 to 62 given later or a complementarystrand thereto, and the probes capable of specifically detecting each ofalleles of any single nucleotide polymorphisms that exist in a regionassociated with glaucoma listed in Tables 3 and 4 or Tables 63 to 70given later or a complementary strand thereto are all embraced in theprobe in the present invention. In a case where, for example, theobtained results are based on a single analysis using a microarray inwhich a probe capable of specifically detecting each of alleles of500,000 single nucleotide polymorphisms, or a complementary strandthereto, is detected in a single operation, the probe of the presentinvention is preferably a probe capable of specifically detecting eachof alleles of a single nucleotide polymorphism or a complementary strandthereto, of which p-value is 1×10⁻³ or less, more preferably a probecapable of specifically detecting each of alleles of a single nucleotidepolymorphism or a complementary strand thereto, of which p-value is3×10⁻⁴ or less, even more preferably a probe capable of specificallydetecting each of alleles of a single nucleotide polymorphism or acomplementary strand thereto, of which p-value is 1×10⁻⁴ or less, andeven more preferably a probe capable of specifically detecting each ofalleles of a single nucleotide polymorphism or a complementary strandthereto, of which p-value is 3×10⁻⁵ or less. In a case where pluralanalytical results are combined and obtained according to a method ofmeta-analysis, such as Mantel-Haenszel method, the probe is preferably aprobe capable of specifically detecting each of alleles of a singlenucleotide polymorphism or a complementary strand thereto, of whichp-value is 1×10⁻² or less, more preferably a probe capable ofspecifically detecting each of alleles of a single nucleotidepolymorphism or a complementary strand thereto, of which p-value is3×10⁻³ or less, even more preferably a probe capable of specificallydetecting each of alleles of a single nucleotide polymorphism or acomplementary strand thereto, of which p-value is 1×10⁻³ or less, evenmore preferably a probe capable of specifically detecting each ofalleles of a single nucleotide polymorphism or a complementary strandthereto, of which p-value is 3×10⁻⁴ or less, and even more preferably aprobe capable of specifically detecting each of alleles of a singlenucleotide polymorphism or a complementary strand thereto, of whichp-value is 1×10⁻⁴ or less.

The probe in the present invention preferably contains anallele-specific sequence or a complementary strand thereto, and evenmore preferably in the probe in the present invention, a sequencecontributing to an allele-specific hybridization consists only of anallele-specific sequence or a complementary strand thereto. To the probein the present invention, a spacer or any sequences of several basesthat are not from an allele-specific sequence for the purpose ofproviding stabilization or the like can be added in an end, within therange that the probe is capable of hybridizing to the sequence under thestringent conditions. The added sequence is preferably a sequence thatdoes not take a three-dimensional structure, such as a hairpinstructure.

The probe can be provided with any labels for use in the detection. Anylabels to be provided to the probe that are ordinarily used can be used,and in general, a fluorescent label such as FITC or Cy3, biotin, anenzyme label such as an alkaline phosphatase and horseradish peroxidase,or the like is usable. In a case where a biotin label is used,streptavidin capable of specifically binding to biotin is previouslyprovided with a further detectable label, and the labeled streptavidinis used as a secondary label. A labeled anti-biotin antibody can also beused in place of the labeled streptavidin. As a method of providing alabel to a probe, any known methods may be used, and the methods arewell known to one of ordinary skill in the art. An arbitrary sequencewhich serves as a spacer as mentioned above may be added to the probe,and the spacer may be provided with a label. A reagent for labeling aprobe, a labeled streptavidin, a labeled anti-biotin antibody or thelike is commercially available as a reagent, and can also be purchased.

The probe in the present invention is not limited whether it is adeoxyribonucleic acid, a ribonucleic acid, or a peptide nucleic acid,and a probe containing a mixed sequence thereof is also embraced in thepresent invention, so long as the probe is capable of specificallyhybridizing to a nucleic acid molecule having an allele of interest. Ina case where a probe containing a ribonucleic acid is used as the probein the present invention, in the sequence of the probe in the presentinvention (including a sequence complementary thereto), thymine may readas uracil. In addition, the probe in the present invention may besubjected to chemical modifications as needed, so long as the probe iscapable of specifically hybridizing under stringent conditions to anucleic acid molecule having an allele of interest. As the method ofproviding a chemical label, any known methods may be used.

The probe for the detection can be reacted with the sample in the stateof solution and then detected by a known method, or previouslyimmobilized to a carrier. The probe can take the form of an immobilizedprobe obtained by previously immobilizing a probe corresponding to eachof the alleles of several to several hundred-thousand different singlenucleotide polymorphisms to a location defined on a solid carrier in thenumber of from one to dozen probes per one single nucleotidepolymorphism, reacting a sample to the immobilized probes, scanning asignal generated from a hybridized probe, and analyzing the scanned datawith a computer, which is a so-called microarray. In a case where theprobe takes the form of an immobilized probe, the largest number of theimmobilized probes are limited by immobilization density and area ofimmobilized sites for the probes.

In a case where the probe takes the form of an immobilized probe asdescribed above, signals on the solid phase from the nucleic acidmolecule having a labeled target allele can be detected by previouslylabeling a nucleic acid molecule in a sample by a known method, andbinding the labeled nucleic acid molecule with an immobilized unlabeledprobe in the present invention, or by binding a nucleic acid moleculehaving an allele to be detected to an immobilized unlabeled probe in thepresent invention, and thereafter labeling the product according to aknown method.

The immobilization can be carried out by any of known method, and forexample, a method such as synthetic oligoprint or spottingphotolithograph can be used. Also, the material for the carrier is notlimited, and a generally used material, for example, a polymer such as apolycarbonate or a polystyrene, glass, silicon crystal or the like canbe used. In addition, in order to enhance adhesive strength of thenucleic acids, a carrier may be provided with a coating such ascationization before the immobilization. In addition, in order toprevent nonspecific nucleic acids from being adsorbed to a carrier,blocking can be carried out with a known blocking agent after theimmobilization. The blocking agent as mentioned above may be any ones solong as the blocking agent is capable of controlling the nonspecificnucleic acids from being adsorbed to the carrier, and for example,salmon sperm DNA, Denhardt's solution, Cot-I DNA extracted from humanplacenta, an anionic surfactant such as sodium dodecyl sulfate, anonionic surfactant such as polyoxyethylene sorbitan monolaurate, or thelike can be used.

In addition, in a case where the probe is immobilized, it is possible toconstruct that each of the opposite alleles contained in one sample isdetected under the same operation by immobilizing a probe specific toeach of the alleles opposite to each other on the same carrier. In theconstruction as described above, not only the alleles but also thegenotypes in the samples can be determined.

It is preferable that the probe used in the detection of the allele is aprobe having a length of preferably from 16 to 55 bases, more preferablyfrom 23 to 27 bases or 47 to 53 bases, and even more preferably 25 basesin total of a length of the polymorphic site and some bases before andafter the polymorphic site, the probe containing the polymorphic sitementioned above and a surrounding sequence thereof, or a sequencecomplementary thereto, that the probe is a probe containing thepolymorphic site mentioned above and a 5′-upstream side thereof,preferably a sequence of 49 bases (i.e. a sequence of 50 bases), theprobe containing the polymorphic site mentioned above and a surroundingsequence thereof, or a sequence complementary thereto, or that the probeis a probe containing a sequence of 50 bases on a 5′-upstream side ofthe polymorphic site mentioned above, the probe having a sequenceadjoining the polymorphic site mentioned above, or a sequencecomplementary thereto.

An even more preferred probe used in the detection of the allele is:

-   1) a probe capable of specifically detecting an allele of the single    nucleotide polymorphism, containing the polymorphic site mentioned    above and a sequence of 12 bases each before and after the    polymorphic site, i.e. a sequence of 25 bases in length, and the    probe containing the polymorphic site mentioned above and a    surrounding sequence thereof, or a sequence complementary thereto,    or-   2a) a probe capable of specifically detecting an allele of the    single nucleotide polymorphism, containing the polymorphic site    mentioned above and a sequence of 49 bases on the 5′-upstream side    thereof (i.e. sequence of 50 bases), and the probe containing a    sequence containing the polymorphic site mentioned above or a    sequence complementary thereto, or-   2b) a probe capable of specifically detecting an allele of the    single nucleotide polymorphism, having a sequence of 50 bases on a    5′-upstream side of the polymorphic site mentioned above, and the    probe having a sequence adjoining the polymorphic site mentioned    above, or a sequence complementary thereto.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, the probe usable in the detection is a probecontaining a single nucleotide polymorphism which is located on a 31stbase of a base sequence, wherein the base sequence is at least one basesequence selected from the group consisting of base sequences shown inSEQ ID NOs: 203 to 514 or a complementary sequence thereto, or a partialsequence thereof, and/or a probe having a base sequence containing atleast one base sequence selected from the group consisting of basesequences shown in SEQ ID NOs: 515 to 694 or a complementary sequencethereto, more preferably a probe containing a single nucleotidepolymorphism which is located on a 31st base of a base sequence, whereinthe base sequence is at least one base sequence selected from the groupconsisting of base sequences shown in SEQ ID NOs: 203 to 238 or acomplementary sequence thereto, or a partial sequence thereof, and/or aprobe having a base sequence containing at least one base sequenceselected from the group consisting of base sequences shown in SEQ IDNOs: 515 to 535 or a complementary sequence thereto, and

-   even more preferably a probe containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is at least one base sequence selected    from following Group A consisting of pairs of base sequences a to r    containing a single nucleotide polymorphism or a complementary    sequence thereto, or a partial sequence thereof, and/or a probe    containing a base sequence, wherein the base sequence is at least    one base sequence or a pair of base sequences, selected from Group B    consisting of base sequences aa to rr or pairs of the base    sequences, or a complementary sequence thereto,-   wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs    of sequences corresponds to one single nucleotide polymorphism, and    each of the base sequences is a base sequence containing an allele    opposite to each other of the single nucleotide polymorphism on a    31st base, and-   in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each    of the base sequences or the pairs of the base sequences is a    sequence for the probe or a pair of sequences for the probes, used    in the detection of one single nucleotide polymorphism,-   wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff,    g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and    mm, n and nn, o and oo, p and pp, q and qq, and r and rr    respectively correspond to the same single nucleotide polymorphism,

Group A

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,-   bb: SEQ ID NO: 516,-   cc: SEQ ID NO: 517,-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,-   ee: SEQ ID NO: 519,-   ff: SEQ ID NO: 520,-   gg: SEQ ID NO: 521,-   hh: SEQ ID NO: 522,-   ii: SEQ ID NO: 523,-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525,-   ll: SEQ ID NO: 526,-   mm: SEQ ID NO: 527,-   nn: SEQ ID NO: 528,-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532.

In a case where any one of the single nucleotide polymorphisms is used,especially, it is preferable that in Group A, a probe containing anallele of a single nucleotide polymorphism located on a 31st base of abase sequence is used, wherein the base sequence is at least one basesequence selected from the group consisting of the following basesequences containing a single nucleotide polymorphism:

-   SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ    ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID    NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO:    228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235,    and SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    and in Group B, a probe containing a base sequence containing at    least one base sequence selected from the group consisting of the    following base sequences:-   SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ    ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID    NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO:    527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531,    and SEQ ID NO: 532,-   or a complementary sequence thereto is used.-   Here, these base sequences are sequences corresponding to a probe    used in the detection of a high-risk allele.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, in a case where any two or more single nucleotidepolymorphisms are combined, the probes usable in the detection arepreferably probes containing a single nucleotide polymorphism which islocated on a 31st base of a base sequence, wherein the base sequence isa base sequence containing a single nucleotide polymorphism, selectedfrom the group consisting of base sequences shown in SEQ ID NOs: 203 to514 or a complementary sequence thereto, or a partial sequence thereof,and/or probes having a base sequence containing a base sequence selectedfrom the group consisting of base sequences shown in SEQ ID NOs: 515 to694 or a complementary sequence thereto, wherein the probes are probescorresponding to two or more different single nucleotide polymorphismsthereof,

-   more preferably probes containing a single nucleotide polymorphism    which is located on a 31st base of a base sequence, wherein the base    sequence is a base sequence containing a single nucleotide    polymorphism, selected from the group consisting of base sequences    shown in SEQ ID NOs: 203 to 238 or a complementary sequence thereto,    or a partial sequence thereof, and/or probes having a base sequence    containing a base sequence selected from the group consisting of    base sequences shown in SEQ ID NOs: 515 to 535 or a complementary    sequence thereto, wherein the probes are probes corresponding to two    or more different single nucleotide polymorphisms thereof, and-   even more preferably probes containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence containing a single    nucleotide polymorphism selected from following Group A consisting    of pairs of base sequences a to r containing a single nucleotide    polymorphism or a complementary sequence thereto, or a partial    sequence thereof, and/or two or more different probes having a base    sequence, wherein the base sequence contains base sequences or a    pair of base sequences, selected from Group B consisting of base    sequences aa to rr or pairs of the base sequences, or a    complementary sequence thereto,-   wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs    of sequences corresponds to one single nucleotide polymorphism, and    each of the base sequences is a base sequence containing an allele    opposite to each other of the single nucleotide polymorphism on a    31st base, and-   in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each    of the base sequences or the pairs of the base sequences is a    sequence for the probe or a pair of sequences for the probes, used    in the detection of one single nucleotide polymorphism,-   wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff,    g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and    mm, n and nn, o and oo, p and pp, q and qq, and r and rr    respectively correspond to the same single nucleotide polymorphism,

Group A

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,-   bb: SEQ ID NO: 516,-   cc: SEQ ID NO: 517,-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,-   ee: SEQ ID NO: 519,-   ff: SEQ ID NO: 520,-   gg: SEQ ID NO: 521,-   hh: SEQ ID NO: 522,-   ii: SEQ ID NO: 523,-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525,-   ll: SEQ ID NO: 526,-   mm: SEQ ID NO: 527,-   nn: SEQ ID NO: 528,-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532,-   even more preferably probes containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence containing a single    nucleotide polymorphism selected from Group A listed above    consisting of pairs of the base sequences containing the single    nucleotide polymorphism or a complementary sequence thereto, or a    partial sequence thereof, and/or probes having a base sequence,    wherein the base sequence contains a base sequence selected from    Group B listed above consisting of pairs of the base sequences or a    complementary sequence thereto, wherein the probes are probes    corresponding to 10 or more different single nucleotide    polymorphisms thereof, and-   even more preferably probes containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence containing a single    nucleotide polymorphism selected from Group A listed above    consisting of pairs of the base sequences containing the single    nucleotide polymorphism or a complementary sequence thereto, or a    partial sequence thereof, and/or probes having a base sequence,    wherein the base sequence contains a base sequence selected from    Group B listed above consisting of pairs of the base sequences or a    complementary sequence thereto, wherein the probes are probes    corresponding to all the different single nucleotide polymorphisms    thereof.

In addition, it is preferable that the single nucleotide polymorphismsto be used in combination are those that are not in the state of linkagedisequilibrium, and from this viewpoint, in all the embodiments of thecombinations mentioned above, supposing that, in Group A, a groupcomposed of a base sequence containing a single nucleotide polymorphismwhich is located on a 31st base of a base sequence, wherein the basesequence is a base sequence belonging to the group consisting of:

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 1,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 2,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 3,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 4, and-   that in Group B,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533, and-   bb: SEQ ID NO: 516,-   or a complementary sequence thereto, is named as a base sequence of    Group 1,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   cc: SEQ ID NO: 517, and-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534-   or a complementary sequence thereto, is named as a base sequence of    Group 2,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525, and-   ll: SEQ ID NO: 526,-   or a complementary sequence thereto, is named as a base sequence of    Group 3, and-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532,-   or a complementary sequence thereto, is named as a base sequence of    Group 4,-   it is preferable to use-   a probe containing any one of the base sequences in Group 1 in a    case that the base sequences belonging to Group 1 are used,-   a probe containing any one of the base sequences in Group 2 in a    case that the base sequences belonging to Group 2 are used,-   a probe containing any one of the base sequences in Group 3 in a    case that the base sequences belonging to Group 3 are used, and/or-   a probe containing any one of the base sequences in Group 4 in a    case that the base sequences belonging to Group 4 are used.

Further, in all the embodiment of the combinations mentioned above, inGroup A, a probe containing an allele of a single nucleotidepolymorphism located on a 31st base of a base sequence, wherein the basesequence is a base sequence containing a single nucleotide polymorphismselected from the group consisting of the following base sequencescontaining a single nucleotide polymorphism:

-   SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ    ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID    NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO:    228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235,    and SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    is preferred, and-   in Group B, a probe containing a base sequence containing a base    sequence selected from the group consisting of the following base    sequences:-   SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ    ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID    NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO:    527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531,    and SEQ ID NO: 532,-   or a complementary sequence thereto is preferred.-   Here, these base sequences are sequences corresponding to a probe    used in the detection of a high-risk allele.

The probe in a case where a Taqman method is used in the detection of anallele usually has a length of preferably from 10 to 300 bases, andcontains the polymorphic site mentioned above and a surrounding sequencethereof, or a sequence complementary thereto, and the probe alsocontains a fluorescent substance and a quencher. More preferably, theprobe has a length of 20 to 60 bases, and contains the polymorphic sitementioned above and a surrounding sequence thereof, or a sequencecomplementary thereto, and the probe contains a fluorescent substanceand a quencher.

The probes in a case where an Invader method is used in the detection ofan allele comprise a probe (reporter) which have a common sequence to a3′-side of the polymorphic site mentioned above and a sequence on a5′-side being completely different therefrom, and a probe (invader) onlycomposed of the common sequence to a 5′-side. These probes usually havea length of preferably from 10 to 300 bases, and more preferably alength of from 20 to 60 bases.

The probe in a case where a LightCycler method is used in the detectionof an allele, usually has a length of preferably from 10 to 300 bases,and contains the polymorphic site mentioned above and a surroundingsequence thereof, or a sequence complementary thereto, and the probecontains a fluorescent substance and a quencher. More preferably, theprobe has a length of 20 to 60 bases, and contains the polymorphic sitementioned above and a surrounding sequence thereof, or a sequencecomplementary thereto, and the probe contains a fluorescent substanceand a quencher.

The probe in a case where a cyclin probe method is used in the detectionof an allele is a probe in which DNA sequences are bound in a mannerthat both ends of an RNA sequence having the polymorphic site and asurrounding sequence thereof, or a sequence complementary thereto, aresandwiched, and each of DNA ends has a fluorescent substance or aquencher. These probes usually have a length of preferably from 10 to300 bases, and contain the polymorphic site mentioned above and asurrounding sequence thereof, or a sequence complementary thereto. Morepreferably, the probe has a length of 20 to 60 bases, and contains thepolymorphic site mentioned above and a surrounding sequence thereof, ora sequence complementary thereto.

The probes in a case where an MPSS method is used in the detection of anallele comprise an oligo DNA (encoded adaptor probe) having a protrudingend of 4 bases on a 5′-side, subsequently a recognition sequence for arestriction enzyme BbvI, and a single-stranded sequence to which adecoder probe is bound on a 3′-side, and a single strand oligo DNA(decoder probe) which has fluorescent substance on a 3′-side, andcontaining 4 different sequences, each sequence specifically hybridizingto one of the encoded adaptor probes. Here, a DNA sequence is bound in amanner that both ends of an RNA sequence having the polymorphic sitementioned above and a surrounding sequence thereof, or a sequencecomplementary thereto, are sandwiched, and each of DNA ends has afluorescent substance or a quencher. The encoded adaptor probe usuallyhas a length of preferably from 10 to 300 base pairs, and morepreferably from 15 to 40 base pairs. On the other hand, the decoderprobe usually has a length of preferably from 10 to 300 base pairs, andmore preferably from 5 to 30 base pairs.

(Kit of Detecting Allele Associated with Glaucoma)

In another embodiment of the present invention, a kit of detecting asingle nucleotide polymorphism associated with glaucoma is provided.

The kit of the present invention (or a composition for predicting arisk) embraces all those kits so long as the allele or genotype of anyone of single nucleotide polymorphisms associated with glaucomadisclosed in the present invention can be detected in a nucleic acidmolecule in a sample. As mentioned above, the kit of the presentinvention may be those that detect a base of either the sense strand orthe antisense strand of the single nucleotide polymorphism, or thosethat detect bases of both the strands. In a case where the kit of thepresent invention is based on the results obtained in a single analysisusing a microarray for a kit of detecting an allele or genotypeassociated with glaucoma for detecting, for example, 500,000 singlenucleotide polymorphisms in a single operation, the kit is preferably akit of detecting an allele or genotype associated with glaucoma forsingle nucleotide polymorphisms having a p-value of 1×10⁻⁴ or lesslisted in Tables 1 and 2 set forth below, more preferably a kit ofdetecting an allele or genotype associated with glaucoma for singlenucleotide polymorphisms having a p-value of 3×10⁻⁴ or less, even morepreferably a kit of detecting an allele or genotype associated withglaucoma for single nucleotide polymorphisms having a p-value of 1×10⁻⁴or less, and even more preferably a kit of detecting an allele orgenotype associated with glaucoma for single nucleotide polymorphismshaving a p-value of 3×10⁻⁵ or less. In a case where the plural analyticresults are combined and obtained according to a method ofmeta-analysis, such as Mantel-Haenszel method, the kit is preferably akit of detecting an allele or genotype associated with glaucoma forsingle nucleotide polymorphisms having a p-value listed in Tables 52 toB set forth below of 1×10⁻² or less, more preferably a kit of detectingan allele or genotype associated with glaucoma for single nucleotidepolymorphisms having a p-value of 3−10⁻³ or less, even more preferably akit of detecting an allele or genotype associated with glaucoma forsingle nucleotide polymorphisms having a p-value of 1×10⁻³ or less, evenmore preferably a kit of detecting an allele or genotype associated withglaucoma for single nucleotide polymorphisms having a p-value of 3×10⁻⁴or less, and even more preferably a kit of detecting an allele orgenotype associated with glaucoma for single nucleotide polymorphismshaving a p-value of 1×10⁻⁴ or less.

A kit of detecting both an allele identified in a high frequency in theglaucoma patient group mentioned above and an allele opposite to theallele is also one embodiment of the present invention. In a case wherea kit as described above is used, as already explained, a genotype ofeach of the alleles can also be determined.

By detecting the presence of an allele or a genotype that is identifiedin a high frequency in glaucoma patients in the sample using the kit ofthe present invention, a future onset risk of glaucoma of an individualnot having glaucoma at the present stage can be predicted, whether ornot precise visual field examinations for glaucoma are required can bedetermined, or the diagnosis of an individual who is suspected ofglaucoma can be made for glaucoma.

In addition, as mentioned above, a kit for determining alleles that areopposite to each other in a single operation can be prepared by using aprobe specific to each of the alleles that are opposite to each other,and providing different labels to the probes, or providing in the formof a microarray or beads array as mentioned above.

The precision for the prediction of the onset risk of glaucoma or thedetermination of whether or not precise visual field examinations arerequired can also be improved by providing a kit having the constitutionof detecting these plural alleles or genotypes using one sample. Even inthe constitution as described above, a constitution can be taken thatthe detection is carried out in a single operation by having the form ofprobes provided with different labels, or the form of the microarray orbeads array mentioned above.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, the kit usable in detecting or predicting a riskis

-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule containing a single    nucleotide polymorphism which is located on a 31st base of a base    sequence, wherein the base sequence is at least one base sequence    selected from the group consisting of base sequences shown in SEQ ID    NOs: 203 to 514 or a complementary sequence thereto, or a partial    sequence thereof, and/or-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising a base sequence    containing at least one base sequence selected from the group    consisting of base sequences shown in SEQ ID NOs: 515 to 694 or a    complementary sequence thereto, more preferably a kit of detecting a    single nucleotide polymorphism associated with the onset of glaucoma    or a kit of predicting an onset risk of glaucoma, using a nucleic    acid molecule containing a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is at least one base sequence selected from the group consisting of    base sequences shown in SEQ ID NOs: 203 to 238 or a complementary    sequence thereto, or a partial sequence thereof, and/or a kit of    detecting a single nucleotide polymorphism associated with the onset    of glaucoma or a kit of predicting an onset risk of glaucoma, using    a nucleic acid molecule comprising a base sequence containing at    least one base sequence selected from the group consisting of base    sequences shown in SEQ ID NOs: 515 to 535 or a complementary    sequence thereto, even more preferably a kit of detecting a single    nucleotide polymorphism associated with the onset of glaucoma or a    kit of predicting an onset risk of glaucoma, using a nucleic acid    molecule containing a single nucleotide polymorphism which is    located on a 31st base of a base sequence, wherein the base sequence    is at least one base sequence selected from following Group A    consisting of pairs of base sequences a to r containing a single    nucleotide polymorphism or a complementary sequence thereto, or a    partial sequence thereof, and/or-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising a base sequence    containing at least one base sequence or a pair of base sequences,    selected from Group B consisting of base sequences aa to rr or pairs    of the base sequences, or a complementary sequence thereto,-   wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs    of sequences corresponds to one single nucleotide polymorphism, and    each of the base sequences is a base sequence containing an allele    opposite to each other of the single nucleotide polymorphism on a    31st base, and-   in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each    of the base sequences or the pairs of the base sequences is a    sequence for the nucleic acid molecule or a pair of sequences for    the nucleic acid molecule, used in the detection of one single    nucleotide polymorphism,-   wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff,    g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and    mm, n and nn, o and oo, p and pp, q and qq, and r and rr    respectively correspond to the same single nucleotide polymorphism,

Group A

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,-   bb: SEQ ID NO: 516,-   cc: SEQ ID NO: 517,-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,-   ee: SEQ ID NO: 519,-   ff: SEQ ID NO: 520,-   gg: SEQ ID NO: 521,-   hh: SEQ ID NO: 522,-   ii: SEQ ID NO: 523,-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525,-   ll: SEQ ID NO: 526,-   mm: SEQ ID NO: 527,-   nn: SEQ ID NO: 528,-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532.

In a case where any one of the single nucleotide polymorphisms is used,especially, in Group A, preferred is a kit of detecting a singlenucleotide polymorphism associated with the onset of glaucoma orpredicting an onset risk of glaucoma, using a nucleic acid moleculecontaining an allele of a single nucleotide polymorphism located on a31st base of a base sequence, wherein the base sequence is at least onebase sequence selected from the group consisting of the following basesequences containing a single nucleotide polymorphism:

-   SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ    ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID    NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO:    228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235,    and SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    and in Group B, preferred is a kit of detecting a single nucleotide    polymorphism associated with the onset of glaucoma or predicting an    onset risk of glaucoma, using a nucleic acid molecule comprising a    base sequence containing a base sequence selected from the group    consisting of the following base sequences:-   SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ    ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID    NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO:    527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531,    and SEQ ID NO: 532,-   or a complementary sequence thereto.-   Here, these base sequences are sequences corresponding to a nucleic    acid molecule used in the detection of a high-risk allele.

In the method of detecting a single nucleotide polymorphism associatedwith glaucoma and the method of predicting an onset risk of glaucoma inthe present invention, in a case where any two or more single nucleotidepolymorphisms are combined, the kit usable in detecting or predicting arisk is

-   preferably a kit of detecting a single nucleotide polymorphism    associated with the onset of glaucoma or a kit of predicting an    onset risk of glaucoma, using a nucleic acid molecule comprising a    single nucleotide polymorphism which is located on a 31st base of a    base sequence, wherein the base sequence is a base sequence    containing a single nucleotide polymorphism, selected from the group    consisting of base sequences shown in SEQ ID NOs: 203 to 514 or a    complementary sequence thereto, or a partial sequence thereof,    and/or-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising a base sequence    containing a base sequence selected from the group consisting of    base sequences shown in SEQ ID NOs: 515 to 694 or a complementary    sequence thereto, wherein the kit is a kit corresponding to two or    more different single nucleotide polymorphisms thereof,-   more preferably a kit of detecting a single nucleotide polymorphism    associated with the onset of glaucoma or a kit of predicting an    onset risk of glaucoma, using a nucleic acid molecule comprising a    single nucleotide polymorphism which is located on a 31st base of a    base sequence, wherein the base sequence is a base sequence    containing a single nucleotide polymorphism, selected from the group    consisting of base sequences shown in SEQ ID NOs: 203 to 218 or a    complementary sequence thereto, or a partial sequence thereof,    and/or-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising a base sequence    containing a base sequence selected from the group consisting of    base sequences shown in SEQ ID NOs: 515 to 535 or a complementary    sequence thereto, wherein the kit is a kit corresponding to two or    more different single nucleotide polymorphisms thereof,-   even more preferably a kit of detecting a single nucleotide    polymorphism associated with the onset of glaucoma or a kit of    predicting an onset risk of glaucoma, using a nucleic acid molecule    comprising a single nucleotide polymorphism which is located on a    31st base of a base sequence, wherein the base sequence is a base    sequence containing a single nucleotide polymorphism, selected from    the group consisting of the following pairs of base sequences    containing a single nucleotide polymorphism or a complementary    sequence thereto, or a partial sequence thereof, and/or a kit of    detecting a single nucleotide polymorphism associated with the onset    of glaucoma or a kit of predicting an onset risk of glaucoma, using    a nucleic acid molecule comprising a base sequence, wherein the base    sequence contains a base sequence or a pair of base sequences,    selected from Group B consisting of base sequences aa to rr or pairs    of the base sequences, or a complementary sequence thereto, wherein    the kit is a kit corresponding to two or more different single    nucleotide polymorphisms thereof,-   wherein in pairs of SEQ ID NOs: shown in a to r, each of the pairs    of sequences corresponds to one single nucleotide polymorphism, and    each of the base sequences is a base sequence containing an allele    opposite to each other of the single nucleotide polymorphism on a    31st base, and-   in SEQ ID NOs: shown in aa to rr or pairs of the SEQ ID NOs:, each    of the base sequences or the pair of base sequences is a sequence    for the nucleic acid molecule or a pair of sequences for the nucleic    acid molecule, used in the detection of one single nucleotide    polymorphism,-   wherein a and aa, b and bb, c and cc, d and dd, e and ee, f and ff,    g and gg, h and hh, i and ii, j and jj, k and kk, l and ll, m and    mm, n and nn, o and oo, p and pp, q and qq, and r and rr    respectively correspond to the same single nucleotide polymorphism,

Group A

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204,-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208,-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   e: SEQ ID NO: 211 and/or SEQ ID NO: 212,-   f: SEQ ID NO: 213 and/or SEQ ID NO: 214,-   g: SEQ ID NO: 215 and/or SEQ ID NO: 216,-   h: SEQ ID NO: 217 and/or SEQ ID NO: 218,-   i: SEQ ID NO: 219 and/or SEQ ID NO: 220,-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224,-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   m: SEQ ID NO: 227 and/or SEQ ID NO: 228,-   n: SEQ ID NO: 229 and/or SEQ ID NO: 230,-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238, and

Group B

-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533,-   bb: SEQ ID NO: 516,-   cc: SEQ ID NO: 517,-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534,-   ee: SEQ ID NO: 519,-   ff: SEQ ID NO: 520,-   gg: SEQ ID NO: 521,-   hh: SEQ ID NO: 522,-   ii: SEQ ID NO: 523,-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525,-   ll: SEQ ID NO: 526,-   mm: SEQ ID NO: 527,-   nn: SEQ ID NO: 528,-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532,-   even more preferably a kit of detecting a single nucleotide    polymorphism associated with the onset of glaucoma or a kit of    predicting an onset risk of glaucoma, using a nucleic acid molecule    comprising a single nucleotide polymorphism which is located on a    31st base of a base sequence, wherein the base sequence is a base    sequence containing a single nucleotide polymorphism, selected from    Group A consisting of pairs of the base sequences containing a    single nucleotide polymorphism listed above or a complementary    sequence thereto, or a partial sequence thereof, and/or a kit of    detecting a single nucleotide polymorphism associated with the onset    of glaucoma or a kit of predicting an onset risk of glaucoma, using    a nucleic acid molecule comprising a base sequence containing a base    sequence selected from Group B consisting of pairs of the base    sequences listed above or a complementary sequence thereto, wherein    the kit is a kit corresponding to ten or more different single    nucleotide polymorphisms thereof, and-   even more preferably a kit of detecting a single nucleotide    polymorphism associated with the onset of glaucoma or a kit of    predicting an onset risk of glaucoma, using a nucleic acid molecule    comprising a single nucleotide polymorphism which is located on a    31st base of a base sequence, wherein the base sequence is a base    sequence containing a single nucleotide polymorphism, selected from    Group A consisting of pairs of the base sequences containing a    single nucleotide polymorphism listed above or a complementary    sequence thereto, or a partial sequence thereof, and/or a kit of    detecting a single nucleotide polymorphism associated with the onset    of glaucoma or a kit of predicting an onset risk of glaucoma, using    a nucleic acid molecule comprising a base sequence containing a base    sequence selected from Group B consisting of pairs of the base    sequences listed above or a complementary sequence thereto, wherein    the kit is a kit corresponding to all the different single    nucleotide polymorphisms thereof.

In addition, it is preferable that the single nucleotide polymorphismsto be used in combination are those that are not in the state of linkagedisequilibrium, and from this viewpoint, in all the embodiments of thecombinations mentioned above, supposing that, in Group A, a groupcomposed of a base sequence containing a single nucleotide polymorphismwhich is located on a 31st base of a base sequence, wherein the basesequence is a base sequence belonging to the group consisting of:

-   a: SEQ ID NO: 203 and/or SEQ ID NO: 204, and-   b: SEQ ID NO: 205 and/or SEQ ID NO: 206,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 1,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   c: SEQ ID NO: 207 and/or SEQ ID NO: 208, and-   d: SEQ ID NO: 209 and/or SEQ ID NO: 210,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 2,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   j: SEQ ID NO: 221 and/or SEQ ID NO: 222,-   k: SEQ ID NO: 223 and/or SEQ ID NO: 224, and-   l: SEQ ID NO: 225 and/or SEQ ID NO: 226,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 3,-   a group composed of a base sequence containing a single nucleotide    polymorphism which is located on a 31st base of a base sequence,    wherein the base sequence is a base sequence belonging to the group    consisting of:-   o: SEQ ID NO: 231 and/or SEQ ID NO: 232,-   p: SEQ ID NO: 233 and/or SEQ ID NO: 234,-   q: SEQ ID NO: 235 and/or SEQ ID NO: 236, and-   r: SEQ ID NO: 237 and/or SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    is named as a base sequence of Group 4, and-   that in Group B,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   aa: SEQ ID NO: 515 and/or SEQ ID NO: 533, and-   bb: SEQ ID NO: 516,-   or a complementary sequence thereto, is named as a base sequence of    Group 1,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   cc: SEQ ID NO: 517, and-   dd: SEQ ID NO: 518 and/or SEQ ID NO: 534-   or a complementary sequence thereto, is named as a base sequence of    Group 2,-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   jj: SEQ ID NO: 524,-   kk: SEQ ID NO: 525, and-   ll: SEQ ID NO: 526,-   or a complementary sequence thereto, is named as a base sequence of    Group 3, and-   a group composed of a base sequence containing a base sequence    belonging to the group consisting of:-   oo: SEQ ID NO: 529,-   pp: SEQ ID NO: 530 and/or SEQ ID NO: 535,-   qq: SEQ ID NO: 531, and-   rr: SEQ ID NO: 532,-   or a complementary sequence thereto, is named as a base sequence of    Group 4,-   it is preferable to use-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising any one of the    base sequences in Group 1 when the base sequences belonging to Group    1 are used,-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising any one of the    base sequences in Group 2 when the base sequences belonging to Group    2 are used,-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising any one of the    base sequences in Group 3 when the base sequences belonging to Group    3 are used, and/or-   a kit of detecting a single nucleotide polymorphism associated with    the onset of glaucoma or a kit of predicting an onset risk of    glaucoma, using a nucleic acid molecule comprising any one of the    base sequences in Group 4 when the base sequences belonging to Group    4 are used.

In all the combinations mentioned above, in Group A, preferred is a kitof detecting a single nucleotide polymorphism associated with the onsetof glaucoma or a kit of predicting an onset risk of glaucoma, using anucleic acid molecule comprising an allele of a single nucleotidepolymorphism located on a 31st base of a base sequence, wherein the basesequence is a base sequence containing a single nucleotide polymorphism,selected from the group consisting of the following base sequencescontaining a single nucleotide polymorphism:

-   SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 208, SEQ ID NO: 209, SEQ    ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 216, SEQ ID NO: 218, SEQ ID    NO: 219, SEQ ID NO: 221, SEQ ID NO: 224, SEQ ID NO: 226, SEQ ID NO:    228, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 234, SEQ ID NO: 235,    and SEQ ID NO: 238,-   or a complementary sequence thereto, or a partial sequence thereof,    and-   in Group B, preferred is a kit of detecting a single nucleotide    polymorphism associated with the onset of glaucoma or a kit of    predicting an onset risk of glaucoma, using a nucleic acid molecule    comprising a base sequence containing a base sequence selected from    the group consisting of the following base sequences:-   SEQ ID NO: 533, SEQ ID NO: 516, SEQ ID NO: 517, SEQ ID NO: 518, SEQ    ID NO: 519, SEQ ID NO: 520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID    NO: 523, SEQ ID NO: 524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO:    527, SEQ ID NO: 528, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO: 531,    and SEQ ID NO: 532,-   or a complementary sequence thereto.-   Here, these base sequences are sequences corresponding to a nucleic    acid molecule used in the detection of a high-risk allele.

(Method of Predicting Onset Risk of Glaucoma, Including Performing thePredicting Risk in Two-Steps or Multi-Steps)

When a prediction of an onset risk of glaucoma using a single nucleotidepolymorphism in the present invention is carried out, it can beperformed in two or more steps as follows; candidates who are consideredthat precise prediction of an onset risk of glaucoma is necessary areselected, and the candidates are subjected to detailed prediction of arisk.

In a case where prediction of a risk is performed in two or moremulti-steps, first, prediction of an onset risk of glaucoma mentionedabove is preformed on at least one single nucleotide polymorphism in thepresent invention, preferably any one or several single nucleotidepolymorphisms, and subsequently, prediction of detailed risks may beperformed using a combination of the single nucleotide polymorphisms ofthe present invention mentioned above. The number of combinations may befurther increased as occasion demands, whereby precision of theprediction of a risk can also be improved. As described above, byperforming prediction of a risk in two or more multi-steps, thereduction in costs for performing the prediction of a risk and theprediction of a risk in a high precision can be both accomplished.

The prediction of a risk in an initial step may be a convenient methodof predicting a risk. For example, a method of predicting a risk so thatan immobilized probe capable of detecting at least one of the singlenucleotide polymorphisms, preferably any one or several singlenucleotide polymorphisms, is immobilized in a manner that at least oneof the single nucleotide polymorphisms in the present invention isdetectable is a convenient method, and can be realized at a low cost.Here, as to a method for nucleic acid extraction in this case, a kitthat can be realized according to a known technique, or a commerciallyavailable simple kit for nucleic acid extraction can be used. It isconvenient to use a method including the steps of using, for example, anenzyme-labeled probe as the immobilized probe used in the prediction ofa risk as described above, and detecting the probe according to acolorimetric method. As to the samples used in the detection, those thatare obtained in a relatively low penetration, such as saliva, oralmucosa cells, urine, hair root, blood or white blood cells arepreferred.

The prediction of a risk in a next step may be a method of predicting arisk with an emphasis on precision. For example, the detection of asingle nucleotide polymorphism associated with the onset of glaucoma iscarried out by combining two or more single nucleotide polymorphisms inthe present invention mentioned above, whereby prediction of a risk maybe performed in a high precision.

By performing prediction of a risk in two or more multi-steps, theprecision for prediction of a risk can be improved, while reducing thecosts or lowering a burden on a subject at an initial step to a minimumlevel.

According to the method disclosed in the present invention, thedetermination can be made that an individual who has an allele orgenotype on the genome that is identified in a high frequency inglaucoma patients disclosed in the present invention has a high risk ofthe onset of glaucoma in future, and that an individual who does nothave an allele or genotype that is identified in a high frequency in theglaucoma patients has a low risk of the onset of glaucoma in future.

In addition, an individual having an allele or genotype on the genomethat is identified in a high frequency in glaucoma patients disclosed inthe present invention has a possibility of being in an early stage ofglaucoma that is difficult to be diagnosed according to a simple methodof determination of glaucoma, such as measurement of intraocularpressure or examination of ocular fundus, and that is diagnosed for thefirst time after performing visual field examination. Therefore, asingle nucleotide polymorphism in the present invention is detected,whereby whether or not the visual field examination is required can bescreened. On the other hand, in a case where an individual who issuspected of being glaucoma has an allele or genotype associated withglaucoma in the present invention on the genome, there is a highprobability that the individual who is suspected of being glaucoma is tobe diagnosed as glaucoma.

Examples

The present invention will be specifically described hereinbelow byExamples, and Examples are given for illustration purposes for a bettercomprehension of the present invention, without intending to limit thescope of the present invention thereto. Here, in the following Examples,as to generally used molecular biological methods that are notspecifically described in detail, methods and conditions described in atextbook such as Molecular Cloning (Joseph Sambrook et al., MolexularCloning—A Laboratory Manual, 3rd Edition, Cold Spring Harbor LaboratoryPress, 2001) or the like are used.

In the present invention, a total DNA was extracted from blood of eachof patients diagnosed as glaucoma, and non-patients diagnosed as beingnot with glaucoma and determined not to have any family history inglaucoma according to a medical interview, and gene loci associated withthe disease were analyzed based on about 500,000 known single nucleotidepolymorphisms on the human genome as an index to determine anassociation of a single nucleotide polymorphism and the disease. Inaddition, patients with fast progression of glaucoma, i.e. progressiveglaucoma cases, and patients with slow progression of glaucoma, i.e.nonprogressive glaucoma cases were subjected to the identification of asingle nucleotide polymorphism and the association of the singlenucleotide polymorphism with the progression in the same manner asabove.

Example 1 DNA Extraction from Specimens

In DNA extraction from specimens, a commercially available automatednucleic acid extraction apparatus (QUIAGEN, BIOROBOT (registeredtrademark) EZ1), and a kit for extraction of a nucleic acid (EZ1 DNABlood 350 μl Kit) compatible to the extraction apparatus and in whichnucleic acids absorbed to magnetic beads were collected by a magneticforce were used. A total DNA was extracted in accordance with theinstruction manuals of the apparatus and kit. According to the presentmethod, a total DNA of about 5 μg was obtained from 350 μL of a bloodspecimen.

Example 2 Analysis of Single Nucleotide Polymorphism

In the analysis of single nucleotide polymorphisms, a commerciallyavailable microarray type single nucleotide polymorphism analysis kit(Affimetrix (GeneChip(registered trademark) Human Mapping 500K)(hereinafter also referred to as microarray) capable of analyzing about500,000 known single nucleotide polymorphisms on the human genome wasused. In the detection of single nucleotide polymorphisms, a scanner(Affimetrix (GeneChip(registered trademark) Scanner 3000)) compatible tothe kit was used. In the analysis of single nucleotide polymorphisms, aspecialized analysis software (Affimetrix (GTYPE(registered trademark)))was used.

The total DNA extracted in Example 1 was treated in accordance with theinstruction manuals of the kit and apparatus, and applied to amicroarray, and a single nucleotide polymorphism existing on the DNAextracted from the specimen was analyzed. Briefly explaining, a sampleobtained by treating 250 ng of a total DNA with a restriction enzymeNspI and a sample obtained by treating 250 ng of a total DNA with arestriction enzyme StyI were prepared, and amplified by a PCR methodwith adaptors bound to the protruding ends of each of the samples. A PCRproduct was collected, and fragmented with DNaseI, and the ends of thefragmented PCR products were biotin-labeled using the labeling reagentcontained in the kit. A buffer for hybridization was added to the PCRproducts that were already fragmented at both ends and labeled, themixture was heat-treated at 99° C. for 10 minutes, and incubated at 49°C. for 1 minute, and the resulting mixture was injected to a microarrayfor NspI-treated sample or a microarray for StyI-treated sampledepending on a firstly treated restriction enzyme, and hybridized at 49°C. for 16 to 18 hours. After the termination of hybridization, themicroarray was stained with streptavidin-phycoerythrin. A fluorescencefrom phycoerythrin bound via biotin and streptavidin to DNA ends ofsamples hybridized with an immobilized allele-specific probe was readusing the scanner mentioned above, and analyzed with the softwarementioned above. Probes corresponding to about 250,000 single nucleotidepolymorphisms each are previously immobilized to the microarray forNspI-treated sample and the microarray for StyI-treated sample,respectively, and analytical results for about 500,000 single nucleotidepolymorphisms per one sample were obtained by combination of both theresults. According to the present method, opposite alleles of each ofthe single nucleotide polymorphisms were read with a single operation,and consequently, a genotype was determined. In this case, it wasdetermined that the genotype was a heterozygote in a case where bothsignals from each of the alleles constituting a single nucleotidepolymorphism were detected, and that the genotype was a homozygote ofthe detected allele in a case where only either one of the signals wasdetected.

Here, in accordance with the instruction manual of the kit, as the probeimmobilized to the kit, a probe for a sense strand or a probe for anantisense strand of the genome is used. In addition, according to thedatasheet of the kit, the determination results for the present kitusing 270 samples and those in HapMap are compared for single nucleotidepolymorphisms overlapping between single nucleotide polymorphismsreported in the HapMap project and single nucleotide polymorphisms inthe kit. As a result, a concordance rate of the single nucleotidepolymorphisms shows 99% or more.

Example 3 Comparison of Single Nucleotide Polymorphisms Between GlaucomaPatients and Non-Patients

The comparison on single nucleotide polymorphisms associated with adisease was made in accordance with the method used in the studies ongenes responsible for age-related macular degeneration by Klein et al(Science, 308, 385, 2005).

Primary open-angle glaucoma patients and normal tension glaucomapatients that were diagnosed on the basis of Guidelines offered by JapanGlaucoma Society were assigned to a glaucoma patient group, and healthyindividuals that were confirmed to have no family history of glaucomaaccording to a medical interview were assigned to a non-patient group.Blood donated under the consent on free will of the participants afterhaving sufficiently explained the contents of studies from 418 cases ofthe glaucoma patient group and 300 controls of the non-patient group wasused as specimens, a total DNA was extracted from the specimensaccording to the method described in Example 1, and the analysis ofsingle nucleotide polymorphisms was performed according to the methoddescribed in Example 2. The analytical results of a single nucleotidepolymorphism obtained in each of the patients were stored in theLaboratory Information Management System (World Fusion, LaboServer)adopting a relational database. A specialized analysis program for asingle nucleotide polymorphism was created and loaded within the system,and the analysis was performed as follows: A single nucleotidepolymorphism considered to have a high experimental reliability wasextracted by rejecting a single nucleotide polymorphism having a callrate of less than 90% in both the glaucoma patient group and thenon-patient group, a single nucleotide polymorphism having a differencein call rates between the glaucoma patient group and the non-patientgroup by 5% or more, a single nucleotide polymorphism having a minorallele frequency of less than 5%, and a single nucleotide polymorphismthat is determined to deviate from the Hardy-Weinberg's equilibriumunder conditions of a p-value of 1×10⁻⁴ or less according to achi-square test, and allele frequencies and genotype frequencies of thesingle nucleotide polymorphisms were compared between the groups. Theallele frequencies and the genotype frequencies were statisticallycompared according to the chi-square test. As to single nucleotidepolymorphisms showing a p-value of 1×10⁻³ or less, cluster imagesserving as a basis for the determination of a genotype were confirmed.In a case where the determination of a genotype was made regardless ofunclearness of the separation among clusters, the single nucleotidepolymorphism was considered to be a non-subject of the analysis. Inother words, the errors in the determination of a genotype were excludedby this step. The evaluation of the cluster was performed withoutinforming the names of single nucleotide polymorphisms and the criticalrates. Single nucleotide polymorphisms of which allele or genotype showsassociation with glaucoma at a p-value of 1×10⁻⁴ or less, i.e. −log P of4 or more are listed in Tables 1 to 2. Here, the odds ratio forassociation of an allele with a disease, and the odds ratio forassociation of a genotype with a disease in each of the tables,respectively, were calculated on the basis of the following formulas (1)to (5).

Allele Frequency=Number of Detection of an Allele in Group/Total Numberof Detection of Alleles in Group   formula (1)

Genotype Frequency=Number of Detection of a Genotype in Group/TotalNumber of Detection of Genotypes in Group   formula (2)

Odds Ratio for Allele=[(Number of Detection of an Allele Identified inHigh Frequency in Glaucoma Patient Group, in Glaucoma PatientGroup)/(Number of Detection of an Allele Opposite to the AlleleIdentified in High Frequency in Glaucoma Patient Group, in GlaucomaPatient Group)]/[(Number of Detection of the Allele Identified in HighFrequency in Glaucoma Patient Group, in Non-Patient Group)/(Number ofDetection of the Allele Opposite to the Allele Identified in HighFrequency in Glaucoma Patient Group, in Non-Patient Group)]  formula (3)

Odds Ratio for Genotype of Homozygote=[(Number of Detection of aGenotype Having Homozygote of an Allele Identified in High Frequency inGlaucoma Patient Group, in Glaucoma Patient Group)/(Number of Detectionof a Genotype Having Homozygote of an Allele Identified in HighFrequency in Non-Patient Group, in Glaucoma Patient Group)]/[(Number ofDetection of the Genotype Having Homozygote of the Allele Identified inHigh Frequency in Glaucoma Patient Group, in Non-Patient Group)/(Numberof Detection of the Genotype Having Homozygote of the Allele Identifiedin High Frequency in Non-Patient Group, in Non-Patient Group)]  formula(4)

Odds Ratio for Genotype of Heterozygote=[(Number of Detection of aGenotype of Heterozygote in Glaucoma Patient Group)/(Number of Detectionof a Genotype Having Homozygote of an Allele Identified in HighFrequency in Non-Patient Group, in Glaucoma Patient Group)]/[(Number ofDetection of the Genotype Having Homozygote in Non-PatientGroup)/(Number of Detection of the Genotype Having Homozygote of theAllele Identified in High Frequency in Non-Patient Group, in Non-PatientGroup)]  formula (5)

TABLE 1 High-Risk Allele High-Risk Allele Critical rate, Frequency inFrequency in Allele 1/ Physical Allele Glaucoma Non-Patient dbSNP IDAllele 2 Exon, Intron Chromosome Location (−logP) Patient Group Grouprs12632110 A/G SEMA3F Intron18 (NM_004186.2) 3 50199229 4.27 0.54 0.44rs2233476 A/C CYB561D2 Exon1 (NM_007022.3) 3 50363387 5.57 0.55 0.42rs9852677 C/T GNAI2 Intron4 (NM_002070.1) 3 50266621 5.27 0.56 0.44rs2236944 G/T GNAI2 Intron4 (NM_002070.1) 3 50267197 5.00 0.55 0.43rs6786523 A/G CACNA2D2 Intron2 (NM_006030.1) 3 50499225 4.05 0.60 0.49rs1467913 G/T CACNA2D2 Intron2 (NM_006030.1) 3 50500021 4.22 0.60 0.50rs2004243 A/G LOC51337 +641bp (NM_016647.1) 8 143815988 4.46 0.45 0.34rs3761980 C/T SLC26A8 −1529bp (NM_052961.2), 6 36101884 4.12 0.93 0.87SLC26A8 −163bp (NM_138718.1) rs16884919 A/G MAPK14 Intron10(NM_001315.1), 6 36179495 4.12 0.93 0.87 MAPK14 Intron10 (NM_139012.1),MAPK14 Intron9 (NM_139014.1), MAPK14 +982bp (NM_139013.1) rs16883860 C/TMAPK14 Intron1 (NM_139013.1), 6 36110440 4.42 0.94 0.87 MAPK14 Intron1(NM_001315.1), MAPK14 Intron1 (NM_139012.1), MAPK14 Intron1 (NM139014.1) rs10513095 G/T CLSTN2 Intron1 (NM_022131.1) 3 141219021 4.520.84 0.75 rs7081455 A/C PLXDC2 +69770bp (NM_032812.7) 10 20678891 4.330.83 0.74 rs7850541 C/T GBGT1 −11253bp (NM_021996.3) 9 133080108 4.150.76 0.66 rs10116267 C/T PSAT1 Intron5 (NM_021154.3), 9 78151286 4.240.78 0.69 PSAT1 Intron5 (NM_058179.2) rs10116231 A/G PSAT1 Intron5(NM_021154.3), 9 78151153 4.11 0.78 0.69 PSAT1 Intron5 (NM_058179.2)rs6813301 G/T MGC45800 +203455bp (NM_178838.2) 4 183234501 4.16 0.120.06 rs11945595 C/T MGC45800 +201900bp (NM_178838.2) 4 183236056 4.070.12 0.06 rs2049723 A/G SPON1 −17894bp (NM_006108.1) 11 13922920 4.780.76 0.65 rs1159623 C/G CNTN5 Intron2 (NM_014361.2), 11 98877941 4.180.45 0.34 CNTN5 Intron2 (NM_175566.1) rs7109406 A/C CNTN5 Intron2(NM_014361.2), 11 98867701 4.17 0.45 0.35 CNTN5 Intron2 (NM_175566.1)Critical rate, Odds Ratio Odds Ratio Sequence Sequence High-Risk OddsRatio Genotype (Homozygote1) (Heterozygote) Containing Containing dbSNPID Allele (Formula 3) (−logP) (Formula 4) (Formula 5) Allele 1 Allele 2rs12632110 Allele 1 1.54 3.60 2.34 1.71 SEQ ID No: 1 SEQ ID No: 2rs2233476 Allele 1 1.66 4.91 2.75 1.84 SEQ ID No: 3 SEQ ID No: 4rs9852677 Allele 2 1.63 4.62 2.70 1.80 SEQ ID No: 5 SEQ ID No: 6rs2236944 Allele 2 1.61 4.41 2.60 1.84 SEQ ID No: 7 SEQ ID No: 8rs6786523 Allele 1 1.53 3.60 2.46 1.80 SEQ ID No: 9 SEQ ID No: 10rs1467913 Allele 2 1.54 3.73 2.49 1.79 SEQ ID No: 11 SEQ ID No: 12rs2004243 Allele 1 1.58 3.85 2.25 1.78 SEQ ID No: 13 SEQ ID No: 14rs3761980 Allele 2 2.05 3.48 6.40 3.13 SEQ ID No: 15 SEQ ID No: 16rs16884919 Allele 2 2.05 3.48 6.40 3.13 SEQ ID No: 17 SEQ ID No: 18rs16883860 Allele 2 2.14 3.74 6.41 3.00 SEQ ID No: 19 SEQ ID No: 20rs10513095 Allele 2 1.73 3.73 3.02 1.74 SEQ ID No: 21 SEQ ID No: 22rs7081455 Allele 1 1.70 3.91 1.91 0.98 SEQ ID No: 23 SEQ ID No: 24rs7850541 Allele 1 1.60 3.89 3.35 2.33 SEQ ID No: 25 SEQ ID No: 26rs10116267 Allele 1 1.63 3.50 2.18 1.24 SEQ ID No: 27 SEQ ID No: 28rs10116231 Allele 2 1.61 3.37 2.18 1.26 SEQ ID No: 29 SEQ ID No: 30rs6813301 Allele 2 2.24 3.67 2.07 2.45 SEQ ID No: 31 SEQ ID No: 32rs11945595 Allele 2 2.24 3.37 2.04 2.45 SEQ ID No: 33 SEQ ID No: 34rs2049723 Allele 1 1.66 3.96 2.87 1.83 SEQ ID No: 35 SEQ ID No: 36rs1159623 Allele 2 1.55 3.88 2.21 1.84 SEQ ID No: 37 SEQ ID No: 38rs7109406 Allele 2 1.55 4.01 2.17 1.89 SEQ ID No: 39 SEQ ID No: 40

TABLE 2 High-Risk Allele High-Risk Allele Critical rate, Frequency inFrequency in Allele 1/ Physical Allele Glaucoma Non-Patient dbSNP IDAllele 2 Exon, Intron Chromosome Location (−logP) Patient Group Grouprs4763559 C/G KLRA1 +10130bp (NM_006611.1) 12 10622909 4.48 0.75 0.65rs4763531 A/G KLRA1 +3474bp (NM_006611.1) 12 10629565 4.11 0.74 0.65(rs9739469) rs2125094 C/T KLRA1 +11027bp (NM_006611.1) 12 10622012 4.380.74 0.64 rs2233476 A/C CYB561D2 Exon1 (NM_007022.3) 3 50363387 5.570.55 0.42 rs9852677 C/T GNAI2 Intron4 (NM_002070.1) 3 50266621 5.27 0.560.44 rs2236944 G/T GNAI2 Intron4 (NM_002070.1) 3 50267197 5.00 0.55 0.43rs4430902 A/G GULP1 Intron1 (NM_016315.1) 2 189010443 3.57 0.85 0.77rs10804020 C/T GULP1 Intron1 (NM_016315.1) 2 189028382 2.93 0.84 0.77rs13137759 C/T DKFZp686L1814 Intron2 4 84262335 3.39 0.82 0.74(NM_194282.1) rs11737784 A/C DKPZp686L1814 −11708bp 4 84300869 3.15 0.810.74 (NM_194282.1) rs9498701 C/T GRIK2 Intron6 (NM_021956.2), 6102336911 0.93 0.59 0.55 GRIK2 Intron6 (NM_175768.1) rs9322609 A/G GRIK2Intron8 (NM_021956.2), 6 102357540 0.67 0.58 0.55 GRIK2 Intron8(NM_175768.1) rs10130333 A/C CHES1 Intron2 (NM_005197.1) 14 889294993.97 0.69 0.59 rs11133030 C/T FBXO8 +139977bp (NM_012180.1) 4 1753925652.16 0.70 0.63 rs2220757 A/C BARX2 +108243bp (NM_003658.3) 11 1289352681.34 0.71 0.66 rs7109406 A/C CNTN5 Intron2 (NM_014361.2), 11 988677014.17 0.45 0.35 CNTN5 Intron2 (NM_175566.1) rs2347897 C/T LOC402300Intron2 (XM_377974), 7 133937842 2.98 0.39 0.31 CALD1 Intron1(NM_004342.5), CALD1 Intron1 (NM_033138.2), CALD1 Intron1 (NM_033157.2),CALD1 −95572bp (NM_033139.2). CALD1 −95572bp (NM 033140.2) rs7794696 A/GLOC402300 Intron1 (XM_377974), 7 133961274 3.29 0.39 0.30 CALD1 Intron1(NM_004342.5), CALD1 Intron1 (NM_033138.2), CALD1 Intron1 (NM_033157.2),CALD1 −72140bp (NM_033139.2), CALD1 −72140bp (NM 033140.2) rs803594 C/GVGLL2 −7136bp (NM_153453.1), 6 117686278 0.94 0.21 0.18 VGLL2 −7152bp(NM_182645.2) rs762164 A/C RUNX1 Intron5 (NM_001754.2) 21 35140644 0.520.44 0.42 Critical rate, Odds Ratio Odds Ratio Sequence SequenceHigh-Risk Odds Ratio Genotype (Homozygote1) (Heterozygote) ContainingContaining dbSNP ID Allele (Formula 3) (−logP) (Formula 4) (Formula 5)Allele 1 Allele 2 rs4763559 Allele 2 1.62 3.70 2.32 1.34 SEQ ID No: 41SEQ ID No: 42 rs4763531 Allele 1 1.58 3.31 2.29 1.39 SEQ ID No: 43 SEQID No: 44 (rs9739469) rs2125094 Allele 1 1.61 3.59 2.34 1.37 SEQ ID No:45 SEQ ID No: 46 rs2233476 Allele 1 1.66 4.91 2.75 1.84 SEQ ID No: 47SEQ ID No: 48 rs9852677 Allele 2 1.63 4.62 2.70 1.80 SEQ ID No: 49 SEQID No: 50 rs2236944 Allele 2 1.61 4.41 2.60 1.84 SEQ ID No: 51 SEQ IDNo: 52 rs4430902 Allele 1 1.64 4.48 1.14 0.54 SEQ ID No: 53 SEQ ID No:54 rs10804020 Allele 1 1.54 4.10 1.02 0.50 SEQ ID No: 55 SEQ ID No: 56rs13137759 Allele 2 1.58 4.23 1.32 0.64 SEQ ID No: 57 SEQ ID No: 58rs11737784 Allele 2 1.54 4.14 1.25 0.61 SEQ ID No: 59 SEQ ID No: 60rs9498701 Allele 2 1.19 4.10 1.17 0.57 SEQ ID No: 61 SEQ ID No: 62rs9322609 Allele 2 1.14 4.04 1.11 0.55 SEQ ID No: 63 SEQ ID No: 64rs10130333 Allele 1 1.54 4.36 2.73 2.46 SEQ ID No: 65 SEQ ID No: 66rs11133030 Allele 1 1.36 4.01 2.46 2.79 SEQ ID No: 67 SEQ ID No: 68rs2220757 Allele 2 1.26 4.03 0.95 0.50 SEQ ID No: 69 SEQ ID No: 70rs7109406 Allele 2 1.55 4.01 2.17 1.89 SEQ ID No: 71 SEQ ID No: 72rs2347897 Allele 1 1.45 4.05 1.58 2.02 SEQ ID No: 73 SEQ ID No: 74rs7794696 Allele 2 1.49 4.01 1.67 1.99 SEQ ID No: 75 SEQ ID No: 76rs803594 Allele 2 1.24 4.31 0.49 1.90 SEQ ID No: 77 SEQ ID No: 78rs762164 Allele 2 1.12 4.02 1.05 1.98 SEQ ID No: 79 SEQ ID No: 80

Tables 1 and 2 list dbSNP ID number or Affimetrix Array ID numberspecifying known single nucleotide polymorphisms obtained, each of basesconstituting Allele 1 and Allele 2, the exon, intron information (in acase where a single nucleotide polymorphism exists on a gene, the genename and the exon or intron in which SNP exists are shown, and in a casewhere a single nucleotide polymorphism does not exist on a gene,neighboring genes and a distance between the gene and the singlenucleotide polymorphism are shown), the chromosome number at which asingle nucleotide polymorphism exists, the physical location of a singlenucleotide polymorphism, the p-value for an allele according to achi-square test (−log P), the high-risk allele frequencies in theglaucoma patient group and the non-patient group, the type of thehigh-risk allele (indicating whether the high-risk allele is Allele 1 orAllele 2), the odds ratio for an allele, the p-value for a genotypeaccording to a chi-square test (−log P), the odds ratio for a genotypeof a homozygote and the odds ratio for a genotype of a heterozygote, andSEQ ID NO of the sequence containing Allele 1 and Allele 2 in each ofthe polymorphic sites. Here, one of ordinary skill in the art can obtainthe information for sequences or alleles of the single nucleotidepolymorphisms from dbSNP ID number or Affimetrix array ID numbermentioned above.

When the allele or genotype frequencies listed in Tables 1 to 2 werecompared between the non-patients without family history and theglaucoma patients, a statistical difference was found. By determining anallele of any one of these single nucleotide polymorphisms, whether ornot an allele that is identified in a higher frequency in the glaucomapatient group than that of the non-patient group exists in the samplecan be determined.

Specifically, when a first single nucleotide polymorphism listed inTables 1 and 2 is explained as an example, one polymorphic site existsin a nucleic acid molecule shown in SEQ ID NO: 1 or 2 occupying a genelocus homologous to each other. In detail, a single nucleotidepolymorphism is associated with the onset of glaucoma, of which 31stbase is either A (Allele 1) or G (Allele 2), wherein Allele 1 indicatedas a high-risk allele, that is, an allele of being A in the singlenucleotide polymorphism is identified in a high frequency in theglaucoma patient group. Further, using the odds ratio for an allele, orthe odds ratio for a genotype of a homozygote and the odds ratio for agenotype of a heterozygote, the degree of which the risk of a diseaseincreases can be predicted in a case of having the allele or genotype.Similarly, all the sequences disclosed in Tables 1 and 2 have apolymorphic site associated with glaucoma in the sequence, and oneallele or at least one genotype in the polymorphic site is identified ina high frequency in the glaucoma patient group.

According to the above studies, 40 single nucleotide polymorphisms ofwhich alleles or genotypes were associated with glaucoma at a p-value of1×10⁻⁴ or less existing in clusters in relatively adjacent regions onthe genome were found in 21 regions.

The allele or genotype identified in a high frequency in the glaucomapatient group of a single nucleotide polymorphism listed in Tables 1 and2 can be used as a marker showing that an onset risk of glaucoma ishigh. On the other hand, an allele that is opposite to the allele or agenotype other than the genotype can be used as a marker showing that anonset risk of glaucoma is low.

Next, the surrounding regions and/or genes of the single nucleotidepolymorphisms listed in Tables 1 and 2 were determined on the basis ofthe database provided by the HapMap project. In detail, regions in whichsingle nucleotide polymorphisms that were considered to be in a linkagedisequilibrium with the single nucleotide polymorphisms listed in Tables1 and 2 exist were determined, on the basis of the linkagedisequilibrium data in combination of the Japanese and the Chinese inthe HapMap project.

Also, in a case where the single nucleotide polymorphism listed inTables 1 and 2 exists in the linkage disequilibrium region containingthe gene, the physical location and the gene name of the region weredetermined. On the other hand, in a case where the single nucleotidepolymorphism listed in Tables 1 and 2 exists in the linkagedisequilibrium region without containing the gene, only the physicallocation of the region was determined. In addition, in a case where thesingle nucleotide polymorphism listed in Tables 1 and 2 exists on onegene beyond the linkage disequilibrium region, only the gene name wasdetermined.

A single nucleotide polymorphism of which p-value is lowest in eachregion is considered to be a single nucleotide polymorphism representingthe region. Tables 3 and 4 list a single nucleotide polymorphismrepresenting the region, the chromosome number at which the regionexists, the physical location of the region (start point and end point)and the gene name contained in the region.

TABLE 3 Representative SNP (SNP with Lowest p-value of Start Point ofEnd Point of Genes Contained the Region) Chromosome Physical LocationPhysical Location in the Region rs16883860 6 36,014,367 36,248,614SLC26A8 DPRXP2 MAPK14 MAPK13 rs2233476 3 49,952,596 50,516,561 RBM6 RBM5SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3B FLJ38608 C3orf45 IFRD2 HYAL3 NAT6HYAL1 HYAL2 TUSC2 RASSF1 ZMYND10 TUSC4 CYB561D2 TMEM115 CACNA2D2rs2004243 8 143,691,186 143,902,698 ARC AK092432 JRK PSCA LY6K LOC51337C8orf55 SLURP1 LYPDC2 LYNX1 AK126845 LY6D LYPD2 rs10513095 3 — — CLSTN2rs7081455 10 20,663,479 20,716,201 no gene rs7850541 9 134,756,557135,192,865 TSC1 GFI1B LOC158078 GTF3C5 CEL CELP RALGDS GBGT1 OBP2BLOC286310 ABO LOC653163 SURF6

TABLE 4 Representative SNP (SNP with Lowest p-value of Start Point ofEnd Point of Genes Contained the Region) Chromosome Physical LocationPhysical Location in the Region rs7109406 11 — — CNTN5 rs4763559 12 10,535,930 10,724,935 LOC255308 KLRA1 FLJ10292 STYK1 rs10116267 9 — —PSAT1 rs6813301 4 183,058,962 183,243,277  LOC643296 rs2049723 11 13,851,048 14,245,926 SPON1 rs9498701 6 — — GRIK2 rs2233476 3 49,952,596 50,516,561 RBM6 RBM5 SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3BFLJ38608 C3orf45 IFRD2 HYAL3 NAT6 HYAL1 HYAL2 TUSC2 RASSF1 ZMYND10 TUSC4CYB561D2 TMEM115 CACNA2D2 rs10130333 14  88,697,458 89,155,209 CHES1LOC646224 CAP2P1 LOC400236 rs4430902 2 188,904,662 189,286,159  GULP1rs13137759 4  83,800,064 84,215,995 SCD4 SEC31L1 THAP9 DKFZp686L1814COPS4 rs11133030 4 175,234,727 175,450,910  FBXO8 KIAA1712 rs762164 21 35,049,200 35,343,511 RUNX1 rs7109406 11 — — CNTN5 rs2220757 11128,920,427 128,953,084  no gene rs803594 6 117,682,814 117,853,711 VGLL2 ROS1 rs2347897 7 — — CALD1

The region listed in Tables 3 and 4 is a region or gene considered to belinked with a single nucleotide polymorphism listed in Tables 3 and 4which is associated with glaucoma in the present invention, and a singlenucleotide polymorphism which exists in these regions or genes isconsidered to be linked with a single nucleotide polymorphism in thepresent invention. In other words, any single nucleotide polymorphismswhich exist in these regions are linked with the single nucleotidepolymorphism which exists in the region as listed in Tables 3 and 4, andany of these single nucleotide polymorphisms can be used in theprediction of a risk of glaucoma in the same manner.

Also, a single nucleotide polymorphism of which allele or genotype showsassociation with glaucoma at a p-value of 1×10⁻³ or less, i.e. −log P of3 or more, is also listed in Tables 5 to 25.

TABLE 5 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs2139539 COL16A1 +69bp (NM_001856.2) 1 31,786,872 3.99 0.87 rs693421ZP4 −45155bp (NM_021186.2) 1 234,425,131. 3.53 0.55 rs2038845 CACNA1SIntron2 (NM_000069.1) 1 197,799,070 0.57 0.41 rs4040617 LOC284591Intron2 (XM_211529) 1 819,185 0.24 0.17 rs540782 ZP4 −43104bp(NM_021186.2) 1 234,423,080 3.43 0.56 rs2040073 LOC339442 −148785bp(XM_378855) 1 38,498,317 3.58 0.38 rs547984 ZP4 −42951bp (NM_021186.2) 1234,422,927 3.48 0.55 rs10798882 PEF Intron1 (NM_012392.1) 1 31,777,6403.52 0.86 rs2499601 ZP4 −50960bp (NM_021186.2) 1 234,430,936 3.24 0.55rs909002 COL16A1 Intron44 (NM_001856.2) 1 31,808,728 3.47 0.84 rs2147798CACNA1S Intron3 (NM_000069.1) 1 197,793,475 1.22 0.56 rs10752589 CSF3R−53414bp (NM_000760.2), 1 36,671,016 3.61 0.18 CSF3R −53414bp(NM_156038.2), CSF3R −53414bp (NM_156039.2), CSF3R −53414bp(NM_172313.1) rs2236913 PSEN2 Intron5 (NM_000447.1), 1 223,380,860 0.610.35 PSEN2 Intron5 (NM_012486.1) rs10518601 ELTD1 −94220bp (XM_371262) 179,312,758 0.27 0.79 rs17102821 ELTD1 −89304bp (XM_371262) 1 79,307,8420.28 0.80 rs7525498 ELTD1 −102412bp (XM_371262) 1 79,320,950 0.30 0.80rs2359112 MGC15882 +194951bp (NM_032884.2) 1 34,548,776 0.58 0.30rs1892116 ELYS Intron2 (NM_175865.1), 1 243,406,363 3.15 0.75 ELYSIntron2 (NM_015446.1) rs7524405 PEF Intron1 (NM_012392.1) 1 31,777,6723.27 0.84 rs704709 MGC39558 Intron8 (NM_152490.1) 1 231,947,005 3.450.61 rs1951626 SERPINC1 −5704bp (NM_000488.1) 1 170,623,758 3.34 0.38rs11163089 MGC34032 Intron4 (NM_152697.2) 1 75,490,567 3.31 0.85rs10430126 LOC388630 +22072bp (XM_371250) 1 47,934,070 3.10 0.64High-Risk Allele Frequency in Critical rate, Odds Ratio Odds RatioNon-Patient Odds Ratio Genotype (Homozygote) (Heterozygote) dbSNP IDGroup (Formula 3) (−logP) (Formula 4) (Formula 5) rs2139539 0.80 1.753.81 7.12 4.52 rs693421 0.45 1.48 3.77 2.14 2.02 rs2038845 0.39 1.133.76 1.00 1.89 rs4040617 0.15 1.09 3.68 ND 0.75 rs540782 0.46 1.47 3.522.09 1.96 rs2040073 0.29 1.52 3.38 1.93 1.80 rs547984 0.46 1.47 3.352.10 1.88 rs10798882 0.79 1.67 3.35 6.05 3.84 rs2499601 0.46 1.45 3.232.05 1.89 rs909002 0.77 1.63 3.19 4.38 2.94 rs2147798 0.51 1.22 3.141.58 2.09 rs10752589 0.11 1.77 3.13 2.06 1.92 rs2236913 0.33 1.14 3.130.88 1.74 rs10518601 0.78 1.08 3.08 3.51 4.57 rs17102821 0.78 1.09 3.083.52 4.57 rs7525498 0.78 1.09 3.04 3.53 4.54 rs2359112 0.27 1.15 3.035.23 0.86 rs1892116 0.67 1.49 2.91 2.89 2.07 rs7524405 0.77 1.59 2.893.77 2.54 rs704709 0.52 1.48 2.83 2.20 1.39 rs1951626 0.30 1.49 2.662.33 1.43 rs11163089 0.77 1.61 2.55 2.70 1.75 rs10430126 0.55 1.45 2.542.08 1.33

TABLE 6 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs16865980 RNF144 +120346bp (NM_014746.2) 2 7,255,254 1.98 0.24rs4953262 PRKCE Intron1 (NM_005400.2) 2 45,952,444 0.15 0.53 rs10170220GULP1 Intron2 (NM_016315.1) 2 189,123,624 2.80 0.84 rs6717705 VITIntron1 (NM_053276.2) 2 36,838,198 2.80 0.88 rs759428 VIT Intron1(NM_053276.2) 2 36.844,694 2.76 0.88 rs4670589 VIT Intron1 (NM_053276.2)2 36,840,872 2.72 0.88 rs10931358 GULP1 Intron2 (NM_016315.1) 2189,096,087 2.69 0.84 rs11124532 VIT Intron1 (NM_053276.2) 2 36,840,5802.65 0.88 rs828868 MGC22014 Intron8 (XM_371501) 2 74,236,159 3.37 0.66rs11677028 LOC339789 Intron9 (NM_207358.1) 2 8,309,297 1.34 0.71rs6431929 LOC339789 +41877bp (NM_207358.1) 2 8,255,994 1.22 0.69rs2421844 SLC4A5 Intron5 (NM_033323.2), 2 74,451,749 3.42 0.48 SLC4A5Intron5 (NM_133478.1), SLC4A5 Intron5 (NM_133479.1), SLC4A5 Intron1(NM_021196.2) rs7559118 FLJ34870 Intron4 (NM_207481.1) 2 133,706,7622.37 0.64 rs17754672 PELI1 −61125bp (NM_020651.2) 2 64,312,259 2.49 0.24rs7584987 QPCT +129689bp (NM_012413.2) 2 37,641,805 2.56 0.44 rs7571760CDC42EP3 +127985bp (NM_006449.3) 2 37,654,409 3.06 0.40 rs6724538 QPCT+127553bp (NM_012413.2) 2 37,639,669 3.33 0.42 rs13387588 SLC4A5 Intron2(NM_033323.2), 2 74,473,795 3.27 0.48 SLC4A5 Intron2 (NM_133478.1),SLC4A5 Intron2 (NM_133479.1), SLC4A5 −19990bp (NM_021196.2) rs7601299SP110 Intron3 (NM_004509.2), 2 230,903,499 1.26 0.91 SP110 Intron3(NM_080424.1), SP110 Intron3 (NM_004510.2) High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs16865980 0.18 1.41 3.96 0.84 1.99 rs4953262 0.52 1.043.75 1.01 0.53 rs10170220 0.78 1.53 3.68 1.03 0.53 rs6717705 0.82 1.603.62 18.77 14.09 rs759428 0.82 1.59 3.58 18.68 14.12 rs4670589 0.82 1.593.57 18.77 14.29 rs10931358 0.77 1.52 3.55 1.02 0.53 rs11124532 0.821.58 3.50 18.48 14.14 rs828868 0.57 1.47 3.48 2.06 1.10 rs11677028 0.661.26 3.45 2.50 2.92 rs6431929 0.65 1.24 3.43 2.32 2.78 rs2421844 0.381.48 3.43 2.39 1.13 rs7559118 0.56 1.37 3.34 2.15 2.25 rs17754672 0.171.49 3.27 6.36 1.11 rs7584987 0.37 1.39 3.26 2.40 1.03 rs7571760 0.311.46 3.13 2.69 1.17 rs6724538 0.32 1.48 3.12 2.49 1.16 rs13387588 0.391.46 3.10 2.29 1.15 rs7601299 0.88 1.39 3.08 ND ND

TABLE 7 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs1198825 RAMP1 −3950bp (NM_005855.1) 2 238,546,337 3.82 0.44 rs10930321STK39 −102538bp (NM_013233.1) 2 169,032,150 3.70 0.44 SNP_A-2170785LTBP1 Intron2 (NM_206943.1), 2 33,090,031 1.24 0.78 LTBP1 −181297bp(NM_000627.2) rs12611812 CNTNAP5 Intron3 (NM 130773.2), 2 124,776,3441.80 0.59 CNTNAP5 Intron3 (NM_138996.1) rs11123034 CNTNAP5 Intron3(NM_130773.2), 2 124,776,617 1.80 0.59 CNTNAP5 Intron3 (NM_138996.1)rs7581836 SLC4A5 −7735bp (NM_033323.2), 2 74,489,052 3.18 0.49 SLC4A5−7735bp (NM_133478.1), SLC4A5 −7735bp (NM_133479.1), SLC4A5 −35247bp(NM_021196.2) rs4430896 KBTBD9 −239670bp (XM_496546) 2 23,246,431 3.580.75 rs7574012 QPCT +126765bp (NM_012413.2) 2 37,638,881 3.04 0.41rs9309484 DCTN1 +1471bp (NM_023019.1), 2 74,498,466 3.06 0.49 DCTN1+1471bp (NM_004082.2) rs4666488 ODD −128777bp (NM_145260.1) 2 19,608,7773.13 0.36 rs3771738 SLC4A5 Intron5 (NM_033323.2), 2 74,452,572 3.04 0.48SLC4A5 Intron5 (NM_133478.1), SLC4A5 Intron5 (NM_133479.1), SLC4A5Intron1 (NM_021196.2) rs4848607 FLJ14816 −60027bp (NM_032845.1) 2120,999,954 3.28 0.75 rs4668312 LOC389059 −20365bp (XM_374017) 2171,432,334 3.04 0.74 rs4411759 HTLF Intron2 (NM_002158.2) 2 48,468,1333.16 0.55 rs2268794 SRD5A2 Intron1 (NM_000348.2) 2 31,691,055 3.01 0.20rs11676168 HTLF Intron1 (NM_002158.2) 2 48,465,842 3.15 0.55 High-RiskAllele Frequency in Critical rate, Odds Ratio Odds Ratio Non-PatientOdds Ratio Genotype (Homozygote) (Heterozygote) dbSNP ID Group (Formula3) (−logP) (Formula 4) (Formula 5) rs1198825 0.34 1.52 3.07 2.23 1.57rs10930321 0.34 1.51 3.04 2.42 1.40 SNP_A-2170785 0.73 1.27 3.01 3.213.52 rs12611812 0.52 1.30 3.00 1.52 0.79 rs11123034 0.52 1.30 3.00 1.520.79 rs7581836 0.40 1.45 2.95 2.24 1.17 rs4430896 0.66 1.54 2.94 1.911.12 rs7574012 0.32 1.45 2.81 2.49 1.22 rs9309484 0.40 1.44 2.77 2.161.16 rs4666488 0.28 1.48 2.67 1.90 1.65 rs3771738 0.40 1.43 2.65 2.141.19 rs4848607 0.66 1.50 2.58 2.33 1.61 rs4668312 0.65 1.47 2.58 1.801.08 rs4411759 0.46 1.44 2.57 2.07 1.57 rs2268794 0.13 1.63 2.55 5.021.46 rs11676168 0.46 1.44 2.52 2.07 1.54

TABLE 8 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs4667649 SP5 +8390bp (XM_371581) 2 171,408,395 3.21 0.73 rs6745010LRP1B +648365bp (NM_018557.1) 2 140,174,363 3.09 0.91 rs2356232 SP5+12276bp (XM_371581) 2 171,412,281 3.19 0.73 rs7608898 SP5 +23719bp(XM_371581) 2 171,423,724 3.19 0.73 rs10184230 LOC389059 −25058bp(XM_374017) 2 171,427,641 3.19 0.73 rs6433243 LOC389059 −21697bp(XM_374017) 2 171,431,002 3.19 0.73 rs10930437 SP5 +6843bp (XM_371581) 2171,406,848 3.15 0.73 rs1566993 DPP10 +503127bp (NM_020868.1) 2116,821,290 3.13 0.96 rs1990702 LRP2 +8346bp (NM_004525.1) 2 169,802,0223.04 0.71 rs10183959 NEDL2 Intron1 (XM_038999) 2 197,139,030 3.15 0.93rs6746374 LOC389059 −7686bp (XM_374017) 2 171,445,013 3.03 0.74rs6599252 SCN10A Intron12 (NM_006514.1) 3 38,764,695 0.14 0.48 rs7612549LOC285307 +209732bp (XM_211837) 3 34,789,105 2.18 0.44 rs1012728FLJ22419 Intron4 (NM_024697.1) 3 21,519,300 2.60 0.49 rs13097360 GBE1−805292bp (NM_000158.1) 3 82,698,727 1.55 0.82 rs33954719 SGEF Intron6(NM_015595.2) 3 155,359,077 1.70 0.65 rs1462840 LOC285194 +426618bp(XM_379207) 3 118,345,185 2.84 0.63 rs17013665 LOC440947 −8774bp(XM_496633) 3 23,718,507 3.79 0.71 rs2044757 SGEF Intron5 (NM_015595.2)3 155,352,950 1.58 0.65 rs1503075 ALCAM −279337bp (NM_001627.1) 3106,289,543 3.46 0.13 rs6550308 LOC285307 +332200bp (XM_211837) 334,911,573 3.08 0.48 rs12494849 CACNA2D2 Intron2 (NM_006030.1) 350,499,562 3.61 0.59 rs3755827 ZNF312 −1350bp (NM_018008.2) 3 62,335,4113.69 0.81 rs9881866 ALCAM −264171bp (NM_001627.1) 3 106,304,709 3.320.15 rs34329202 LOC389099 −54783bp (XM_371621) 3 22,240,837 3.37 0.92rs10935365 CLSTN2 Intron1 (NM_022131.1) 3 141,227,766 3.47 0.84High-Risk Allele Frequency in Critical rate, Odds Ratio Odds RatioNon-Patient Odds Ratio Genotype (Homozygote) (Heterozygote) dbSNP IDGroup (Formula 3) (−logP) (Formula 4) (Formula 5) rs4667649 0.65 1.492.43 1.93 1.23 rs6745010 0.86 1.75 2.42 3.69 2.17 rs2356232 0.65 1.492.41 1.92 1.23 rs7608898 0.65 1.48 2.41 1.92 1.23 rs10184230 0.65 1.482.41 1.92 1.23 rs6433243 0.65 1.48 2.41 1.92 1.23 rs10930437 0.64 1.482.40 1.92 1.22 rs1566993 0.91 2.10 2.40 4.55 2.22 rs1990702 0.63 1.462.36 2.00 1.32 rs10183959 0.88 1.89 2.35 3.17 1.72 rs6746374 0.66 1.472.34 1.95 1.25 rs6599252 0.47 1.04 3.94 1.17 0.56 rs7612549 0.36 1.353.93 2.38 0.88 rs1012728 0.41 1.39 3.84 1.76 2.08 rs13097360 0.77 1.343.22 0.56 0.32 rs33954719 0.58 1.30 3.07 2.09 2.33 rs1462840 0.54 1.423.07 2.23 2.03 rs17013665 0.62 1.53 3.05 2.42 1.69 rs2044757 0.59 1.283.05 2.03 2.32 rs1503075 0.07 1.93 3.01 ND 1.84 rs6550308 0.39 1.44 2.981.90 1.78 rs12494849 0.49 1.48 2.89 2.20 1.52 rs3755827 0.73 1.61 2.882.43 1.51 rs9881866 0.09 1.81 2.87 1.97 1.97 rs34329202 0.86 1.83 2.821.99 1.01 rs10935365 0.76 1.61 2.77 2.61 1.62

TABLE 9 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs2138789 GRK7 Intron2 (NM_139209.1) 3 142,991,449 3.33 0.14 rs6550783LOC440947 −8191bp (XM_496633) 3 23,719,090 3.18 0.69 rs779701 GRM7Intron7 (NM_181875.1), 3 7,493,772 3.03 0.33 GRM7 Intron7 (NM_000844.2),GRM7 Intron7 (NM_181874.1) rs2216524 IL1RAP Intron7 (NM_134470.2), 3191,824,803 3.03 0.86 IL1RAP Intron7 (NM_002182.2) rs3922704 FLJ31579Intron3 (NM_153268.1) 3 112,983,875 3.06 0.88 rs7641653 LOC389105−266407bp (XM_374037) 3 35,093,422 3.06 0.40 rs2193877 IL1RAP Intron7(NM_134470.2), 3 191,825,144 3.05 0.85 IL1RAP Intron7 (NM_002182.2)rs4624606 IL1RAP Intron9 (NM_002182.2), 3 191,836,948 3.07 0.84 IL1RAP+6172bp (NM_134470.2) rs4858594 THRB Intron2 (NM_000461.2) 3 24,248,8583.02 0.69 rs10454254 LOC285441 Intron1 (XM_379295) 4 187,735,925 1.170.81 rs13110551 CCRN4L −116225bp (NM_012118.2) 4 140,178,323 2.59 0.58rs1503539 MAD2L1 +168679bp (NM_002358.2) 4 121,169,516 3.91 0.38rs3804100 TLR2 Exon2 (NM_003264.2) 4 154,983,014 3.96 0.74 rs4516662CCRN4L −116103bp (NM_012118.2) 4 140,178,445 2.22 0.57 rs10009731 STX18−141961bp (NM_016930.2) 4 4,803,808 2.34 0.83 rs7676755 CYP4V2 Intron2(NM_207352.1) 4 187,490,196 0.68 0.80 rs10517556 LOC391656 −135832bp(XM_373027) 4 62,947,647 2.42 0.51 rs16996478 UNC5C −11150bp(NM_003728.2) 4 96,838,490 3.98 0.20 rs10517578 LOC285533 Intron4(NM_173662.1) 4 155,005,757 3.89 0.74 rs34415360 LOC132391 −118159bp(XM_497978) 4 117,081,308 3.45 0.29 rs930438 CENPC1 +97050bp(NM_001812.1) 4 68,069,912 3.27 0.82 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs2138789 0.08 1.86 2.67 3.28 1.88 rs6550783 0.61 1.472.48 2.18 1.51 rs779701 0.25 1.48 2.48 1.80 1.64 rs2216524 0.79 1.592.47 1.99 1.18 rs3922704 0.82 1.66 2.44 2.09 1.20 rs7641653 0.32 1.452.43 2.08 1.50 rs2193877 0.79 1.59 2.41 2.15 1.30 rs4624606 0.78 1.582.40 2.50 1.59 rs4858594 0.61 1.45 2.21 1.95 1.33 rs10454254 0.77 1.273.70 0.60 0.33 rs13110551 0.50 1.38 3.56 2.22 2.18 rs1503539 0.28 1.563.53 3.05 1.40 rs3804100 0.64 1.57 3.37 2.72 1.84 rs4516662 0.50 1.343.27 2.08 2.12 rs10009731 0.77 1.46 3.23 6.58 5.41 rs7676755 0.78 1.183.22 3.26 4.09 rs10517556 0.43 1.37 3.21 1.75 1.96 rs16996478 0.12 1.803.17 3.11 1.79 rs10517578 0.65 1.56 3.15 2.47 1.61 rs34415360 0.21 1.573.01 3.26 1.28 rs930438 0.75 1.57 2.84 3.33 2.31

TABLE 10 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs17279573 KIAA0922 +22425bp (NM_015196.2) 4 154,937,893 3.34 0.68rs11727442 TLR2 −23144bp (NM_003264.2) 4 154,943,527 3.42 0.69 rs1027690MAD2L1 +191047bp (NM_002358.2) 4 121,147,148 3.22 0.43 rs16891164LOC441009 +88767bp (XM_498965) 4 14,590,288 3.15 0.96 rs13107767LOC152519 +6607bp (NM_207330.1) 4 47,886,619 3.44 0.60 rs1980391LOC389239 −207565bp (XM_371714) 4 165,986,419 3.18 0.62 rs7376639LOC132391 −82192bp (XM_497978) 4 117,117,275 3.04 0.29 rs4256218 SCD4Intron1 (NM_024906.1) 4 84,047,858 3.28 0.89 rs972469 FSTL5 +959616bp(NM_020116.2) 4 161,703,038 3.06 0.40 rs6829490 TXK +894bp (NM_003328.1)4 47,908,795 3.23 0.57 rs3804099 TLR2 Exon2 (NM_003264.2) 4 154,982,2613.07 0.71 rs4392496 KIAA0922 Intron3 (NM_015196.2) 4 154,800,110 3.100.46 rs4568220 LOC344988 Intron2 (XM_293671) 4 121,413,055 3.23 0.11rs33964061 TXK +1806bp (NM_003328.1) 4 47,907,883 3.11 0.57 rs6447614TXK +804bp (NM_003328.1) 4 47,908,885 3.11 0.57 rs12655405 PDZK3−33552bp (NM_015022.2), 5 31,801,198 0.80 0.93 PDZK3 −33552bp(NM_178140.1) rs4515309 NNT +296580bp (NM_012343.2), 5 44,037,927 1.770.12 NNT +296836bp (NM_182977.1) rs1377489 MTRR +135148bp (NM_024010.1),5 8,089,385 1.15 0.82 MTRR +135148bp (NM_002454.1) rs309593 CSPG2Intron10 (NM_004385.2) 5 82,884,337 3.95 0.43 rs6579788 TCOF1 −25018bp(NM_000356.1) 5 149,692,410 1.15 0.37 rs6451268 FLJ25422 Intron11(NM_145000.2) 5 36,291,121 1.39 0.61 rs529279 C5orf13 −5941bp(NM_004772.1) 5 111,126,776 3.20 0.30 rs298091 PDE4D −114328bp(NM_006203.3) 5 59,032,360 3.58 0.82 rs3097776 FAT2 Intron2(NM_001447.1) 5 150,916,554 3.34 0.72 rs11750584 FLJ40243 −22454bp(NM_173489.2) 5 41,129,616 3.13 0.20 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs17279573 0.60 1.48 2.74 2.31 1.66 rs11727442 0.60 1.492.73 2.22 1.49 rs1027690 0.34 1.46 2.63 2.24 1.45 rs16891164 0.92 2.122.63 ND ND rs13107767 0.50 1.47 2.62 2.07 1.39 rs1980391 0.53 1.45 2.601.99 1.23 rs7376639 0.21 1.52 2.56 2.90 1.27 rs4256218 0.82 1.69 2.552.70 1.59 rs972469 0.32 1.45 2.47 2.27 1.36 rs6829490 0.48 1.45 2.462.04 1.46 rs3804099 0.63 1.46 2.45 2.24 1.57 rs4392496 0.37 1.44 2.412.04 1.47 rs4568220 0.06 2.04 2.40 3.19 2.00 rs33964061 0.48 1.43 2.342.00 1.46 rs6447614 0.48 1.43 2.34 2.00 1.46 rs12655405 0.91 1.33 3.880.13 0.06 rs4515309 0.08 1.56 3.74 0.00 2.02 rs1377489 0.78 1.28 3.5620.15 19.82 rs309593 0.33 1.54 3.45 2.43 1.64 rs6579788 0.32 1.23 3.432.27 0.80 rs6451268 0.56 1.25 3.38 1.85 2.30 rs529279 0.22 1.53 2.903.30 1.31 rs298091 0.74 1.61 2.86 2.37 1.43 rs3097776 0.63 1.49 2.772.01 1.23 rs11750584 0.13 1.64 2.68 1.86 1.80

TABLE 11 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs11748095 FBXL17 −103066bp (NM_022824.1) 5 107,848,076 3.18 0.50rs1428470 LY64 −8157bp (NM_005582.1) 5 66,536,525 3.15 0.80 rs11167493CSF1R +19417bp (NM_005211.2) 5 149,393,634 3.02 0.12 rs6891720 LY64−7944bp (NM_005582.1) 5 66,536,312 3.04 0.80 rs4246764 LY64 −384319bp(NM_005582.1) 5 66,912,687 3.00 0.29 rs429419 ADAMTS12 Intron17(NM_030955.1) 5 33,624,092 3.12 0.91 rs298063 PDE4D −88343bp(NM_006203.3) 5 59,006,375 3.15 0.82 rs818725 ADAMTS12 Intron17(NM_030955.1) 5 33,624,060 3.05 0.91 rs4285312 NEDD9 −191677bp(NM_006403.2), 6 11,532,564 3.28 0.16 NEDD9 −191687bp (NM_182966.1)rs4840196 GRIK2 Intron8 (NM_021956.2), 6 102,359,520 0.96 0.60 GRIK2Intron8 (NM_175768.1) rs4075603 NEDD9 −191609bp (NM_006403.2), 611,532,496 3.09 0.16 NEDD9 −191619bp (NM_182966.1) rs2764236 GRIK2Intron9 (NM_021956.2), 6 102,389,150 0.83 0.59 GRIK2 Intron9(NM_175768.1) rs4840195 GRIK2 Intron8 (NM_021956.2), 6 102,359,490 0.840.59 GRIK2 Intron8 (NM_175768.1) rs372534 AOF1 Intron8 (XM_173173) 618,295,895 3.02 0.68 rs6907963 LOC442154 Intron1 (XM_498036) 6 4,903,4812.45 0.88 rs6916915 EGFL11 −135926bp (NM_198283.1) 6 66,398,533 3.440.54 rs3857597 LOC442216 −86680bp (XM_498099) 6 51,020,014 3.84 0.22rs902287 EGFL11 −127786bp (NM_198283.1) 6 66,390,393 3.31 0.51 rs7761118MAPK14 Intron9 (NM_139013.1), 6 36,176,281 3.63 0.93 MAPK14 Intron9(NM_001315.1), MAPK14 Intron9 (NM_139012.1), MAPK14 Intron9(NM_139014.1) High-Risk Allele Frequency in Critical rate, Odds RatioOdds Ratio Non-Patient Odds Ratio Genotype (Homozygote) (Heterozygote)dbSNP ID Group (Formula 3) (−logP) (Formula 4) (Formula 5) rs117480950.41 1.45 2.66 1.95 1.66 rs1428470 0.72 1.53 2.64 1.93 1.16 rs111674930.07 1.92 2.52 ND 1.77 rs6891720 0.72 1.51 2.52 1.91 1.16 rs4246764 0.211.51 2.46 2.43 1.54 rs429419 0.85 1.76 2.44 3.75 2.20 rs298063 0.75 1.552.44 2.11 1.32 rs818725 0.86 1.74 2.37 3.66 2.17 rs4285312 0.10 1.763.87 1.07 2.27 rs4840196 0.55 1.19 3.72 1.19 0.60 rs4075603 0.10 1.733.67 1.04 2.22 rs2764236 0.56 1.17 3.61 1.15 0.59 rs4840195 0.55 1.173.55 1.18 0.60 rs372534 0.59 1.45 3.50 2.40 2.31 rs6907963 0.83 1.563.18 16.95  13.09  rs6916915 0.45 1.47 3.08 2.18 1.20 rs3857597 0.141.73 3.07 2.60 1.76 rs902287 0.42 1.46 3.05 2.19 1.16 rs7761118 0.871.95 3.05 4.77 2.39

TABLE 12 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs9473926 LOC442216 −10440bp (XM_498099) 6 50,943,774 3.30 0.54rs1206153 KIAA1900 Intron6 (NM_052904.1) 6 97,652,757 3.02 0.56rs16871306 NEDD9 −153598bp (NM_006403.2), 6 11,494,485 3.04 0.09 NEDD9−153608bp (NM_182966.1) rs9398995 ENPP1 Intron1 (NM_006208.1) 6132,181,896 3.12 0.58 rs9358578 LOC389370 Intron1 (XM_374162) 622,810,626 3.27 0.44 rs10488281 PRES Intron2 (NM_206883.1), 7102,663,783 1.13 0.48 PRES Intron2 (NM_206884.1), PRES Intron2(NM_206885.1), PRES Intron2 (NM_198999.1) rs2215164 COBL Intron1(NM_015198.2) 7 51,093,537 1.75 0.88 rs2299257 PON1 Intron4(NM_000446.3) 7 94,587,416 3.65 0.37 rs1075737 PRES Intron2(NM_206883.1), 7 102,665,144 0.99 0.48 PRES Intron2 (NM_206884.1), PRESIntron2 (NM_206885.1), PRES Intron2 (NM_198999.1) rs10232532 CPA5−3205bp (NM_080385.2) 7 129,575,431 0.30 0.52 rs3917538 PON1 Intron5(NM_000446.3) 7 94,582,544 3.50 0.51 rs1222418 FLJ32786 Intron12(NM_144648.1) 7 133,334,253 3.72 0.17 rs2966701 TAS2R41 +27695bp(NM_176883.1) 7 142,720,419 3.59 0.13 rs10271531 HGF +217504bp(NM_000601.3) 7 80,758,592 3.78 0.42 rs12700287 DNAH11 Intron8(NM_003777.1) 7 21,385,860 3.76 0.96 rs10228385 LOC401324 +47600bp(XM_379484) 7 35,236,926 3.79 0.84 rs4726533 PRSS1 −172004bp(NM_002769.2) 7 141,771,615 0.57 0.39 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs9473926 0.45 1.46 2.90 2.17 1.69 rs1206153 0.47 1.432.80 1.95 1.08 rs16871306 0.04 2.17 2.52 ND 2.22 rs9398995 0.48 1.442.51 2.06 1.59 rs9358578 0.35 1.47 2.46 2.12 1.39 rs10488281 0.44 1.213.64 1.66 0.72 rs2215164 0.83 1.44 3.60 0.32 0.17 rs2299257 0.28 1.543.43 2.01 1.80 rs1075737 0.44 1.19 3.41 1.60 0.72 rs10232532 0.50 1.073.24 1.18 1.94 rs3917538 0.42 1.47 3.16 2.20 1.16 rs1222418 0.10 1.893.14 10.10  1.72 rs2966701 0.07 2.01 3.13 2.48 2.15 rs10271531 0.33 1.523.11 2.46 1.41 rs12700287 0.92 2.39 3.10 ND ND rs10228385 0.76 1.65 3.072.21 1.26 rs4726533 0.36 1.13 3.07 1.71 0.72

TABLE 13 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs2285652 OSBPL3 Intron22 (NM_015550.2), 7 24,617,110 3.56 0.84 OSBPL3Intron21 (NM_145320.1), OSBPL3 Intron21 (NM_145321.1), OSBPL3 Intron20(NM_145322.1), OSBPL3 Intron22 (NM_145323.1), OSBPL3 Intron21 (NM145324.1) rs10250170 TPK1 Intron8 (NM_022445.2) 7 143,650,537 0.69 0.12rs2966712 TAS2R41 −7843bp (NM_176883.1) 7 142,683,960 3.22 0.11rs1001148 COBL Intron1 (NM_015198.2) 7 51,094,084 1.40 0.88 rs17167646FLJ32786 Intron16 (NM_144648.1) 7 133,365,708 3.50 0.15 rs930688FLJ32786 Intron16 (NM_144648.1) 7 133,366,047 3.50 0.15 rs991162FLJ32110 −9270bp (NM_181646.2) 7 88,024,134 3.55 0.15 rs2592845LOC401324 +94391bp (XM_379484) 7 35,283,717 3.07 0.77 rs10228514LOC401324 +47709bp (XM_379484) 7 35,237,035 3.55 0.83 rs10488110LOC340268 Intron1 (XM_294634) 7 9,827,710 3.41 0.11 rs975910 HIC+252683bp (NM_199072.2) 7 114,505,890 3.53 0.94 rs2893506 LOC401324+25585bp (XM_379484) 7 35,214,911 3.52 0.83 rs10236415 LOC401324+28462bp (XM_379484) 7 35,217,788 3.52 0.83 rs9640055 GLCCI1 Intron1(XM_166529) 7 7,802,756 3.27 0.82 rs2592860 LOC401324 +14726bp(XM_379484) 7 35,204,052 3.25 0.71 rs6961391 NUP205 −1742bp (XM_371954)7 134,698,206 3.12 0.73 rs115357 FLJ13842 +130801bp (NM_024645.1) 840,376,469 1.62 0.31 rs2977752 LOC441352 +55834bp (XM_499115) 872,715,809 1.84 0.58 rs10504440 LOC389667 +50257bp (XM_372046) 870,255,391 2.06 0.70 rs2470722 GEM −2381bp (NM_005261.2), 8 95,346,1141.12 0.77 GEM −2381bp (NM_181702.1) High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs2285652 0.77 1.64 3.02 3.55 2.33 rs10250170 0.10 1.243.02 0.11 1.67 rs2966712 0.06 1.97 3.02 0.82 2.20 rs1001148 0.84 1.373.01 0.32 0.18 rs17167646 0.09 1.84 2.93 9.85 1.66 rs930688 0.09 1.842.93 9.85 1.66 rs991162 0.09 1.89 2.91 2.49 1.98 rs2592845 0.69 1.512.90 3.17 2.30 rs10228514 0.75 1.62 2.86 2.20 1.30 rs10488110 0.06 2.072.81 ND 1.89 rs975910 0.88 1.98 2.72 5.49 3.05 rs2893506 0.75 1.60 2.692.47 1.58 rs10236415 0.75 1.60 2.69 2.47 1.58 rs9640055 0.75 1.57 2.652.55 1.62 rs2592860 0.63 1.48 2.52 2.15 1.45 rs6961391 0.65 1.47 2.522.11 1.36 rs115357 0.25 1.32 3.49 1.01 1.90 rs2977752 0.52 1.30 3.391.87 2.19 rs10504440 0.64 1.35 3.32 2.77 2.73 rs2470722 0.73 1.25 3.280.79 0.45

TABLE 14 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs12898 CTSB +629bp (NM_001908.2), 8 11,738,607 2.92 0.49 CTSB +629bp(NM_147780.1), CTSB +629bp (NM_147781.1), CTSB +629bp (NM_147782.1),CTSB +629bp (NM 147783.1) rs6991723 ZNF596 +33933bp (NM_173539.1) 8221,272 2.75 0.58 rs16904092 MGC27434 Intron1 (NM_145050.2) 8130,571,112 1.05 0.90 rs6468360 LOC286135 −35034bp (XM_379573) 829,863,536 2.01 0.55 rs4736872 FLJ13842 Intron5 (NM_024645.1) 840,570,858 0.36 0.63 rs10958627 FLJ13842 Intron5 (NM_024645.1) 840,594,675 0.03 0.47 rs16935718 LOC389667 +60391bp (XM_372046) 870,265,525 1.87 0.74 rs1605950 PXMP3 −574113bp (NM_000318.1) 878,649,107 0.82 0.28 rs2513858 STARS −43515bp (NM_139166.2) 8107,895,164 0.07 0.65 rs16935744 LOC389667 +75414bp (XM_372046) 870,280,548 1.80 0.74 rs2272767 CTSB Intron1 (NM_001908.2), 8 11,748,4682.69 0.48 CTSB Intron3 (NM_147780.1), CTSB Intron2 (NM_147781.1), CTSBIntron2 (NM_147782.1), CTSB Intron2 (NM 147783.1) rs705998 LOC389667+90010bp (XM_372046) 8 70,295,144 1.55 0.71 rs12545915 SNTG1 Intron2(NM_018967.1) 8 51,329,479 3.39 0.85 rs6999627 SNTG1 Intron2(NM_018967.1) 8 51,340,728 3.27 0.85 rs3757916 RBPMS Intron9(NM_006867.1) 8 30,545,447 3.10 0.43 rs2729482 LOC169355 Intron9(NM_194294.1) 8 39,975,804 3.50 0.11 rs7823902 LOC286129 Intron2(XM_209910) 8 26,963,854 3.20 0.34 rs11783765 GTF2E2 Intron7(NM_002095.3) 8 30,556,550 3.12 0.40 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs12898 0.40 1.42 3.27 1.81 1.90 rs6991723 0.49 1.40 3.252.08 2.04 rs16904092 0.87 1.33 3.19 0.16 0.09 rs6468360 0.48 1.32 3.161.78 0.86 rs4736872 0.61 1.09 3.12 1.54 2.26 rs10958627 0.47 1.01 3.080.96 1.75 rs16935718 0.68 1.34 3.07 3.16 3.04 rs1605950 0.25 1.19 3.070.78 1.73 rs2513858 0.65 1.02 3.05 1.49 2.29 rs16935744 0.68 1.33 3.043.05 2.98 rs2272767 0.40 1.40 3.01 1.75 1.85 rs705998 0.65 1.29 3.012.51 2.69 rs12545915 0.77 1.62 2.91 1.82 1.01 rs6999627 0.78 1.61 2.771.81 1.02 rs3757916 0.34 1.45 2.62 1.96 1.62 rs2729482 0.06 2.07 2.613.62 2.00 rs7823902 0.26 1.50 2.58 2.12 1.56 rs11783765 0.32 1.46 2.552.17 1.51

TABLE 15 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs17758599 SNTG1 Intron1 (NM_018967.1) 8 51,109,255 3.14 0.85 rs2468705KCNK9 +75721bp (NM_016601.2) 8 140,618,265 3.08 0.28 rs6474298 FLJ13842−168006bp (NM_024645.1) 8 41,042,506 3.23 0.81 rs17473451 TUSC3 −73601bp(NM_006765.2), 8 15,368,500 3.05 0.79 TUSC3 −73601bp (NM_178234.1)rs6559770 SLC28A3 +116711bp (NM_022127.1) 9 84,005,935 2.83 0.47rs10984339 LOC442434 +182746bp (XM_498343) 9 118,798,668 1.63 0.42rs920753 LOC389771 −178380bp(XM_374296) 9 89,862,442 0.11 0.27 rs411102LOC347265 +48076bp (XM_294590) 9 99,196,524 3.28 0.16 rs1342022 ANXA1−61274bp (NM_000700.1) 9 72,935,061 1.37 0.60 rs10972299 VCP +4230bp(NM_007126.2) 9 35,042,331 3.54 0.95 rs303612 LOC340511 −47888bp(XM_295261) 9 103,142,991 0.20 0.61 rs1316814 BARX1 −25445bp(NM_021570.2) 9 93,822,273 3.20 0.57 rs1538844 JMJD2C Intron8(NM_015061.1) 9 6,953,799 3.07 0.41 rs2148591 PCSK5 −63459bp(NM_006200.2) 9 75,671,716 3.11 0.45 rs932881 JMJD2C +1849bp(NM_015061.1) 9 7,167,496 3.25 0.78 rs10764881 MGMT −70674bp(NM_002412.1) 10 131,153,821 0.91 0.72 rs1649035 TFAM +176804bp(NM_003201.1), 10 60,002,707 3.82 0.61 TFAM +187289bp (NM_012251.1)rs782394 LOC387721 −251645bp (XM_370585) 10 130,349,442 2.06 0.54rs1649048 TFAM +168385bp (NM_003201.1), 10 59,994,288 3.54 0.60 TFAM+178870bp (NM_012251.1) rs7477330 TFAM +162217bp (NM_003201.1), 1059,988,120 3.63 0.60 TFAM +172702bp (NM_012251.1) rs17157033 LOC439960−30545bp (XM_498478) 10 44,613,470 2.88 0.96 rs10458653 PCBD −54076bp(NM_000281.1) 10 72,369,768 0.63 0.25 High-Risk Allele Non-Patient OddsRatio Genotype (Homozygote) (Heterozygote) dbSNP ID Group (Formula 3)(−logP) (Formula 4) (Formula 5) rs17758599 0.78 1.59 2.49 2.77 1.78rs2468705 0.20 1.53 2.45 2.48 1.52 rs6474298 0.73 1.55 2.45 2.27 1.48rs17473451 0.71 1.51 2.43 1.98 1.24 rs6559770 0.38 1.41 3.55 1.82 1.96rs10984339 0.36 1.28 3.18 1.34 1.89 rs920753 0.26 1.04 3.13 0.55 1.55rs411102 0.10 1.79 3.06 1.50 2.03 rs1342022 0.54 1.24 3.05 1.34 0.70rs10972299 0.89 2.09 3.01 2.57 15.88  rs303612 0.59 1.05 3.01 1.39 2.12rs1316814 0.48 1.45 2.80 2.27 1.60 rs1538844 0.33 1.46 2.78 1.91 1.70rs2148591 0.36 1.45 2.72 2.28 1.21 rs932881 0.70 1.52 2.53 2.37 1.61rs10764881 0.68 1.20 3.94 5.56 6.03 rs1649035 0.51 1.51 3.94 2.56 2.09rs782394 0.47 1.33 3.70 1.75 0.80 rs1649048 0.51 1.48 3.54 2.36 1.99rs7477330 0.51 1.49 3.52 2.38 1.95 rs17157033 0.92 2.14 3.45 ND NDrs10458653 0.22 1.16 3.45 5.56 0.82

TABLE 16 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs3849969 SEC24C Intron12 (NM_004922.2), 10 75,196,005 3.36 0.27 SEC24CIntron11 (NM_198597.1) rs1658438 TFAM +170686bp (NM_003201.1), 1059.996,589 3.56 0.60 TFAM +181171bp (NM_012251.1) rs1649039 TFAM+174144bp (NM_003201.1), 10 60,000,047 3.59 0.60 TFAM +184629bp(NM_012251.1) rs1658456 TFAM +148429bp (NM_003201.1), 10 59,974,332 3.540.60 TFAM +158914bp (NM_012251.1) rs1649060 TFAM +154583bp(NM_003201.1), 10 59,980,486 3.54 0.60 TFAM +165068bp (NM_012251.1)rs17130394 HABP2 −103263bp (NM_004132.2) 10 115,199,512 3.18 0.84rs10763558 TFAM +186037bp (NM_003201.1), 10 60,011,940 3.62 0.60 TFAM+196522bp (NM_012251.1) rs10763556 TFAM +185501bp (NM_003201.1), 1060,011,404 3.53 0.60 TFAM +195986bp (NM_012251.1) rs7902091 CTNNA3Intron7 (NM_013266.1) 10 68,268,298 2.66 0.51 rs1210065 TMEM23 Intron5(NM_147156.3) 10 51,882,795 2.61 0.41 rs10994838 ACF Intron1(NM_014576.2), 10 52,312,506 1.16 0.36 ACF Intron1 (NM_138932.1), ACFIntron1 (NM_138933.1) rs11189912 SH2D4B +793340bp (NM_207372.1) 1083,189,636 3.27 0.92 rs1028534 TMEM23 Intron3 (NM_147156.3) 1051,898,627 2.47 0.66 rs1203392 TMEM23 Intron5 (NM_147156.3) 1051,874,999 2.46 0.41 rs7910849 LOC220929 +29028bp (NM_182755.1) 1031,144,546 3.06 0.74 rs7904101 TMEM23 −7099bp (NM_147156.3) 1052,060,842 1.38 0.37 rs4474374 LOC439991 −14752bp (XM_495838) 1085,647,711 0.14 0.33 rs11016249 MKI67 −323870bp (NM_002417.2) 10130,138,328 3.24 0.69 High-Risk Allele Frequency in Critical rate, OddsRatio Odds Ratio Non-Patient Odds Ratio Genotype (Homozygote)(Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula 4) (Formula5) rs3849969 0.19 1.57 3.44 1.58 1.92 rs1658438 0.51 1.48 3.43 2.35 1.92rs1649039 0.50 1.48 3.43 2.34 1.91 rs1658456 0.51 1.48 3.40 2.33 1.91rs1649060 0.51 1.48 3.40 2.33 1.91 rs17130394 0.77 1.59 3.40 1.38 0.71rs10763558 0.50 1.49 3.36 2.33 1.87 rs10763556 0.50 1.48 3.34 2.33 1.89rs7902091 0.43 1.39 3.33 1.98 0.94 rs1210065 0.34 1.40 3.31 1.59 1.89rs10994838 0.32 1.23 3.31 2.21 0.80 rs11189912 0.86 1.83 3.15 1.07 0.52rs1028534 0.59 1.38 3.10 2.22 2.21 rs1203392 0.34 1.38 3.08 1.57 1.85rs7910849 0.66 1.48 3.08 1.69 0.93 rs7904101 0.32 1.26 3.05 1.12 1.81rs4474374 0.32 1.04 3.05 1.98 0.69 rs11016249 0.60 1.47 2.90 2.42 1.91

TABLE 17 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs2092832 SH2D4B +843746bp (NM_207372.1) 10 83,240,042 3.58 0.94rs4934425 ANKRD22 Intron1 (NM_144590.1) 10 90,599,698 3.05 0.64rs2688612 PLAU −17730bp (NM_002658.1) 10 75,323,211 3.57 0.42 rs10883820CNNM2 Intron1 (NM_017649.3), 10 104,754,651 3.37 0.90 CNNM2 Intron1(NM_199076.1), CNNM2 +77286bp (NM_199077.1) rs7074084 TFAM +146618bp(NM_003201.1), 10 59,972,521 3.20 0.59 TFAM +157103bp (NM_012251.1)rs1649023 TFAM +129923bp (NM_003201.1), 10 59,955,826 3.11 0.59 TFAM+140408bp (NM_012251.1) rs1649080 TFAM +137397bp (NM_003201.1), 1059,963,300 3.11 0.59 TFAM +147882bp (NM_012251.1) rs1303970 TFAM+142580bp (NM_003201.1), 10 59,968,483 3.11 0.59 TFAM +153065bp(NM_012251.1) rs3829154 ECHDC3 −1630bp (NM_024693.2) 10 11,822,759 3.170.49 rs1926029 NT5C2 Intron11 (NM_012229.2) 10 104,845,660 3.20 0.91rs2802493 LOC283034 +233953bp (XM_210860) 10 43,873,589 3.15 0.39rs718641 ECHDC3 −4475bp (NM_024693.2) 10 11,819,914 3.08 0.49 rs7913781ZWINT −792415bp (NM_007057.2), 10 58,583,444 3.22 0.18 ZWINT −792415bp(NM_032997.1) rs7894588 CNNM2 Intron1 (NM_017649.3), 10 104,746,020 3.080.91 CNNM2 Intron1 (NM_199076.1), CNNM2 +68655bp (NM_199077.1) rs1569868SH2D4B +852561bp (NM_207372.1) 10 83,248,857 3.13 0.93 rs10883843 NT5C2−6408bp (NM_012229.2) 10 104,937,483 3.03 0.91 rs7074395 NT5C2 +2984bp(NM_012229.2) 10 104,834,918 3.00 0.91 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs2092832 0.88 1.99 2.88 3.15 1.55 rs4934425 0.55 1.442.83 2.29 1.86 rs2688612 0.33 1.50 2.81 2.28 1.45 rs10883820 0.84 1.762.78 2.47 1.34 rs7074084 0.49 1.44 2.77 2.16 1.69 rs1649023 0.50 1.442.69 2.13 1.69 rs1649080 0.50 1.44 2.69 2.13 1.69 rs1303970 0.50 1.442.69 2.13 1.69 rs3829154 0.40 1.44 2.61 2.16 1.29 rs1926029 0.85 1.752.57 3.18 1.80 rs2802493 0.31 1.47 2.50 2.27 1.38 rs718641 0.40 1.442.49 2.12 1.30 rs7913781 0.11 1.72 2.46 4.17 1.49 rs7894588 0.85 1.722.46 2.41 1.35 rs1569868 0.88 1.88 2.45 3.12 1.65 rs10883843 0.85 1.712.41 2.39 1.35 rs7074395 0.85 1.71 2.39 2.39 1.35

TABLE 18 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs10829630 MGMT +6919bp (NM_002412.1) 10 131,462,275 3.02 0.58 rs923811BARX2 +93402bp (NM_003658.3) 11 128,920,427 0.82 0.67 rs4937431 BARX2+124127bp (NM_003658.3) 11 128,951,152 1.56 0.44 rs11021202 MGC33371+224211bp (NM_144664.3) 11 94,917,555 3.28 0.14 rs497776 MAML2 Intron1(NM_032427.1) 11 95,597,312 2.23 0.80 rs11602121 LOC399921 Intron4(XM_374904) 11 70,237,526 1.45 0.29 rs11220171 CNTN5 Intron2(NM_014361.2), 11 98,866,995 3.46 0.36 CNTN5 Intron2 (NM_175566.1)rs4307718 LOC440033 +175532bp (XM_498512) 11 23,320,437 3.48 0.96rs1384483 LOC440033 +63001bp (XM_498512) 11 23,207,906 3.23 0.13rs500629 ZBTB16 Intron3 (NM_006006.3) 11 113,550,770 3.13 0.29 rs1507527LOC387754 −33940bp (XM_373490) 11 13,882,655 3.25 0.77 rs2007052 SPON1−37564bp (NM_006108.1) 11 13,903,250 3.21 0.77 rs7935243 PHACS Intron3(NM_032592.1) 11 44,050,992 3.13 0.80 rs562160 CHORDC1 −291532bp(NM_012124.1) 11 89,887,386 3.12 0.82 rs474530 DLG2 Intron1(NM_001364.1) 11 83,930,298 3.02 0.95 rs493622 CHORDC1 −286443bp(NM_012124.1) 11 89,882,297 3.04 0.82 rs610160 GRIA4 Intron3(NM_000829.1) 11 105,202,105 3.06 0.20 rs10844107 BICD1 −37784bp(NM_001714.1) 12 32,113,668 0.28 0.24 rs10862853 LOC387871 +436103bp(XM_373539) 12 83,274,707 1.19 0.82 rs979879 SLC6A15 +353475bp(NM_182767.2), 12 83,403,423 1.63 0.83 SLC6A15 +375211bp (NM_018057.3)rs11116400 SLC6A15 +425437bp (NM_182767.2), 12 83,331,461 1.53 0.83SLC6A15 +447173bp (NM_018057.3) rs2611284 SLC6A15 +335334bp(NM_182767.2), 12 83,421,564 1.66 0.83 SLC6A15 +357070bp (NM_018057.3)High-Risk Allele Frequency in Critical rate, Odds Ratio Odds RatioNon-Patient Odds Ratio Genotype (Homozygote) (Heterozygote) dbSNP IDGroup (Formula 3) (−logP) (Formula 4) (Formula 5) rs10829630 0.49 1.432.21 1.96 1.40 rs923811 0.63 1.17 3.76 0.91 0.49 rs4937431 0.38 1.273.24 2.05 0.85 rs11021202 0.08 1.85 3.18 1.33 2.17 rs497776 0.74 1.423.06 3.58 3.31 rs11602121 0.24 1.30 3.00 5.91 1.01 rs11220171 0.28 1.512.95 2.04 1.67 rs4307718 0.92 2.27 2.90 ND ND rs1384483 0.07 1.90 2.78ND 1.79 rs500629 0.22 1.52 2.72 1.88 1.69 rs1507527 0.69 1.51 2.72 2.231.39 rs2007052 0.68 1.51 2.69 2.24 1.40 rs7935243 0.72 1.53 2.67 2.952.11 rs562160 0.75 1.55 2.57 2.91 2.02 rs474530 0.91 2.00 2.56 ND NDrs493622 0.75 1.54 2.45 2.76 1.89 rs610160 0.14 1.64 2.25 3.19 1.42rs10844107 0.23 1.08 3.48 5.00 0.75 rs10862853 0.78 1.28 3.34 3.97 4.53rs979879 0.78 1.36 3.33 4.41 4.61 rs11116400 0.78 1.34 3.33 4.38 4.65rs2611284 0.78 1.36 3.31 4.41 4.57

TABLE 19 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs10746324 SLC6A15 +349318bp (NM_182767.2), 12 83,407,580 1.61 0.83SLC6A15 +371054bp (NM_018057.3) rs11056970 LMO3 +34143bp (NM_018640.3),12 16,558,431 3.21 0.86 LMO3 +34143bp (NM_001001395.1) rs4766663 OAS1+7223bp (NM_002534.1), 12 111,825,694 3.28 0.20 OAS1 +5266bp(NM_016816.1) rs7134411 FLJ25056 +34943bp (NM_182530.1) 12 68,673,7130.33 0.51 rs1382851 FLJ36004 −92384bp (NM_152590.1) 12 25,689,829 2.110.58 rs7295295 LOC387871 +418915bp (XM_373539) 12 83,257,519 1.84 0.82rs1380405 SLC6A15 +351862bp (NM_182767.2), 12 83.405,036 1.56 0.83SLC6A15 +373598bp (NM_018057.3) rs11116414 SLC6A15 +389377bp(NM_182767.2), 12 83,367,521 1.46 0.83 SLC6A15 +411113bp (NM_018057.3)rs2468302 SLC6A15 +354456bp (NM_182767.2), 12 83,402,442 1.46 0.83SLC6A15 +376192bp (NM_018057.3) rs2555255 LOC144742 +11128bp (XM_378388)12 118,173,222 0.08 0.25 rs2072133 OAS3 Exon16 (NM_006187.2) 12111,871,980 3.71 0.68 rs1647106 THRAP2 +168009bp (NM_015335.2) 12114,691,094 3.67 0.33 rs10779090 LOC387871 +423693bp (XM_373539) 1283,262,297 1.14 0.82 rs2125093 KLRA1 +10392bp (NM_006611.1) 1210,622,647 3.52 0.77 rs900610 MGC50559 Intron2 (NM_173802.2) 1231,707,890 3.14 0.16 rs10772350 STYK1 −7029bp (NM_018423.1) 1210,724,935 3.08 0.71 rs4767030 OAS1 +3826bp (NM_002534.1), 12111,822,297 3.40 0.21 OAS1 +1869bp (NM_016816.1) rs1647110 THRAP2+163373bp (NM_015335.2) 12 114,695,730 3.37 0.29 High-Risk AlleleFrequency in Critical rate, Odds Ratio Odds Ratio Non-Patient Odds RatioGenotype (Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP)(Formula 4) (Formula 5) rs10746324 0.78 1.36 3.29 4.38 4.57 rs110569700.79 1.63 3.27 3.21 3.17 rs4766663 0.13 1.68 3.12 12.40 1.52 rs71344110.49 1.08 3.12 1.17 0.61 rs1382851 0.51 1.33 3.10 1.86 2.07 rs72952950.76 1.38 3.09 4.09 4.00 rs1380405 0.79 1.35 3.08 4.25 4.38 rs111164140.79 1.33 3.07 4.21 4.42 rs2468302 0.79 1.33 3.07 4.21 4.42 rs25552550.24 1.03 3.04 3.04 0.72 rs2072133 0.59 1.51 3.03 2.27 1.46 rs16471060.24 1.56 3.02 2.29 1.63 rs10779090 0.78 1.27 3.01 3.58 4.04 rs21250930.68 1.54 2.92 2.11 1.27 rs900610 0.10 1.75 2.91 1.47 1.98 rs107723500.62 1.47 2.83 1.91 1.11 rs4767030 0.14 1.68 2.81 3.49 1.66 rs16471100.21 1.56 2.76 2.29 1.62

TABLE 20 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs1859336 OAS3 −8940bp (NM_006187.2) 12 111,830,029 3.06 0.21 rs1700369LOC441646 Intron8 (XM_497358) 12 126,367,113 3.00 0.95 rs7134391 OAS1+10940bp (NM_002534.1), 12 111,829,411 3.09 0.20 OAS1 +8983bp(NM_016816.1) rs2270152 VWF Intron49 (NM_000552.2) 12 5,931,330 3.160.86 rs4767040 OAS3 −2232bp (NM_006187.2) 12 111,836,737 3.07 0.20rs10774679 OAS3 −1501bp (NM_006187.2) 12 111,837,468 3.06 0.20rs11104300 HGNT-IV-H-287319bp (NM_013244.2) 12 86,022,432 3.05 0.21rs10735079 OAS3 Intron2 (NM_006187.2) 12 111,842,728 3.03 0.20 rs7961953DKFZp762A217 Intron1 (NM_152588.1) 12 81,594,304 3.02 0.34 rs261912ETNK1 Intron6 (NM_018638.3) 12 22,728,208 3.01 0.85 rs4145280 G30+266246bp (XM_498445) 13 104,643,159 0.25 0.51 rs4772238 CLYBL −20285bp(NM_206808.1), 13 99,202,794 0.14 0.12 CLYBL −20285bp (NM_138280.3)rs9519091 SLC10A2 −518655bp (NM_000452.1) 13 103,035,852 1.56 0.49rs3916959 G30 +269026bp (XM_498445) 13 104,640,379 0.25 0.51 rs9558509G30 +271368bp (XM_498445) 13 104,638,037 0.27 0.51 rs9300981 G30+469126bp (XM_498445) 13 104,440,279 3.79 0.63 rs1606405 SLITRK1+664827bp (NM_052910.1) 13 82,684,518 1.37 0.55 rs10492680 LOC400123−23647bp (XM_378411) 13 39,702,836 3.01 0.93 rs7150435 ALKBH +19861bp(NM_006020.1) 14 77,189,287 0.00 0.53 rs759363 CHES1 Intron3(NM_005197.1) 14 88,828,894 3.89 0.32 rs11159897 CHES1 Intron3(NM_005197.1) 14 88,829,194 3.89 0.32 rs4902116 LOC401778 +110022bp(XM_377343) 14 61,774,890 2.61 0.57 rs2241127 CHES1 Intron2(NM_005197.1) 14 88,892,969 1.47 0.31 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs1859336 0.14 1.63 2.58 4.24 1.57 rs1700369 0.90 1.972.55 1.54 0.71 rs7134391 0.14 1.63 2.50 3.57 1.57 rs2270152 0.80 1.622.48 2.47 1.50 rs4767040 0.14 1.63 2.48 3.56 1.56 rs10774679 0.14 1.632.47 3.58 1.56 rs11104300 0.15 1.61 2.44 3.37 1.52 rs10735079 0.14 1.622.44 3.56 1.55 rs7961953 0.26 1.48 2.43 2.28 1.48 rs261912 0.78 1.582.43 3.04 2.02 rs4145280 0.50 1.06 3.95 1.12 0.55 rs4772238 0.11 1.063.78 0.00 1.53 rs9519091 0.43 1.27 3.58 1.48 2.06 rs3916959 0.50 1.063.58 1.12 0.57 rs9558509 0.50 1.07 3.47 1.13 0.58 rs9300981 0.53 1.523.14 2.32 1.75 rs1606405 0.50 1.24 3.10 1.47 0.74 rs10492680 0.88 1.832.46 6.22 3.50 rs7150435 0.53 1.00 3.42 1.09 1.92 rs759363 0.23 1.593.29 2.36 1.69 rs11159897 0.23 1.59 3.29 2.36 1.69 rs4902116 0.49 1.383.12 1.93 1.98 rs2241127 0.26 1.29 3.11 0.99 1.80

TABLE 21 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs10148022 LOC283584 −265499bp (XM_211108) 14 85,864,556 0.85 0.32rs1571379 SEL1L −289804bp (NM_005065.3) 14 81,359,690 3.60 0.73rs11622536 KCNK10 −72402bp (NM_138318.1), 14 87,879,410 0.64 0.77 KCNX10−20310bp (NM_138317.1), KCNK10 −16406bp (NM_021161.3) rs2816632 BRF1Intron2 (NM_001519.2), 14 104,812,400 3.27 0.21 BRF1 −27133bp(NM_145685.1), BRF1 −26587bp (NM_145696.1) rs1106845 STELLAR +19768bp(XM_375075) 14 35,931,107 3.26 0.11 rs17115925 SEL1L −271331bp(NM_005065.3) 14 81,341,217 3.00 0.72 rs7176242 ATP10A +44699bp(NM_024490.2) 15 23,428,814 0.19 0.85 rs16969520 CIB2 Intron1(NM_006383.2) 15 76,204,239 2.36 0.35 rs10902569 ADAMTS17 Intron3(NM_139057.1) 15 98,663,829 0.08 0.67 rs11071129 UNC13C +173927bp(XM_496070) 15 52,882,022 0.20 0.59 rs1441354 FLJ13710 −290691bp(NM_024817.1) 15 69,517,251 0.22 0.25 rs11631211 ATP10A +61309bp(NM_024490.2) 15 23,412,204 0.22 0.86 rs12592527 UNC13C +174082bp(XM_496070) 15 52,882,177 0.27 0.60 rs4144951 FLJ38736 Intron17(NM_182758.1) 15 51,643,802 3.40 0.16 rs2654216 EFTUD1 +28186bp(NM_024580.3) 15 80,181,440 3.18 0.60 rs8026133 SLCO3A1 −26936bp(NM_013272.2) 15 90,171,014 3.10 0.16 rs4780091 LOC440268 +506bp(XM_496063) 15 31,271,629 3.26 0.63 rs17191316 ANXA2 +144537bp(NM_004039.1) 15 58,282,291 3.23 0.07 rs12597526 USP10 +4263bp(NM_005153.1) 16 83,374,937 1.28 0.38 rs2133803 LOC149329 −13263bp(XM_086494) 16 59,665,671 1.32 0.81 rs288601 CDH8 −492870bp(NM_001796.2) 16 61,120,407 1.81 0.53 rs1819829 FLJ31547 Intron9(NM_145024.1) 16 54,444,785 2.53 0.79 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype(Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula4) (Formula 5) rs10148022 0.29 1.19 3.07 0.84 1.72 rs1571379 0.63 1.533.03 2.22 1.36 rs11622536 0.75 1.16 3.00 0.64 0.38 rs2816632 0.14 1.642.78 4.49 1.36 rs1106845 0.06 2.06 2.71 ND 1.98 rs17115925 0.64 1.462.39 2.22 1.56 rs7176242 0.85 1.07 3.26 0.09 0.06 rs16969520 0.28 1.393.19 1.38 1.86 rs10902569 0.67 1.03 3.10 0.64 0.41 rs11071129 0.58 1.053.08 1.37 2.11 rs1441354 0.24 1.07 3.07 5.71 0.78 rs11631211 0.85 1.083.06 0.10 0.07 rs12592527 0.58 1.07 3.05 1.42 2.13 rs4144951 0.09 1.822.73 2.80 1.87 rs2654216 0.51 1.44 2.57 2.14 1.54 rs8026133 0.10 1.742.48 4.60 1.66 rs4780091 0.54 1.46 2.46 2.02 1.37 rs17191316 0.03 2.612.37 ND 2.22 rs12597526 0.33 1.24 3.91 2.51 0.81 rs2133803 0.76 1.303.52 4.13 4.60 rs288601 0.47 1.30 3.35 1.61 0.77 rs1819829 0.73 1.463.32 4.58 3.80

TABLE 22 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs2541639 HBZ +531bp (NM_005332.2) 16 145,035 2.77 0.22 rs372657LOC283867 −312819bp (XM_378606) 16 64,480,523 3.63 024 rs173840LOC283867 −313113bp (XM_378606) 16 64,480,817 3.63 0.24 rs4843428 FOXL1+137429bp (NM_005250.1) 16 85,308,297 3.20 0.88 rs254353 LOC283867−301507bp (XM_378606) 16 64,469,211 3.33 0.19 rs4077853 PLCG2 Intron27(NM_002661.1) 16 80,528,471 3.16 0.35 rs3859079 CDH13 −112144bp(NM_001257.2) 16 81,105,935 3.17 0.66 rs8062968 LOC283867 −298359bp(XM_378606) 16 64,466,063 3.05 0.24 rs11074523 HS3ST2 Intron1(NM_006043.1) 16 22,734,434 3.11 0.80 rs8045067 WWOX −1063753bp(NM_130844.1), 16 77,754,805 3.35 0.75 WWOX −1063753bp (NM_130791.1),WWOX −1063753bp (NM_016373.1), WWOX −1063753bp (NM_018560.4), WWOX−48197bp (NM_130792.1) rs12443833 WWOX −1063238bp (NM_130844.1), 1677,754,290 3.17 0.72 WWOX −1063238bp (NM_130791.1), WWOX −1063238bp(NM_016373.1), WWOX −1063238bp (NM_018560.4), WWOX −48712bp (NM130792.1) rs1877821 RGS9 −9409bp (NM_003835.1) 17 60,605,875 1.17 0.75rs9896245 RGS9 −11066bp (NM_003835.1) 17 60,604,218 1.45 0.75 rs1029754LOC401887 +487202bp (XM_497555) 17 66,236,699 2.11 0.89 rs17808998 NTN1Intron2 (NM_004822.1) 17 8,919,071 2.23 0.63 rs9895463 SPACA3 −6355bp(NM_173847.2) 17 28,336,640 0.01 0.58 rs11868422 RPH3AL Intron1(NM_006987.2) 17 198,072 3.62 0.21 rs1877823 RGS9 +3136bp (NM_003835.1)17 60,657,405 1.20 0.77 High-Risk Allele Frequency in Critical rate,Odds Ratio Odds Ratio Non-Patient Odds Ratio Genotype (Homozygote)(Heterozygote) dbSNP ID Group (Formula 3) (−logP) (Formula 4) (Formula5) rs2541639 0.16 1.55 3.13 1.23 1.90 rs372657 0.16 1.65 2.84 3.03 1.56rs173840 0.16 1.65 2.84 3.03 1.56 rs4843428 0.81 1.66 2.75 1.89 1.05rs254353 0.12 1.71 2.71 4.73 1.57 rs4077853 0.27 1.49 2.62 2.17 1.57rs3859079 0.58 1.46 2.51 2.17 1.60 rs8062968 0.17 1.57 2.49 1.99 1.68rs11074523 0.73 1.53 2.48 2.40 1.56 rs8045067 0.67 1.52 2.43 2.17 1.49rs12443833 0.63 1.48 2.38 2.11 1.45 rs1877821 0.71 1.25 3.80 3.21 3.78rs9896245 0.70 1.29 3.65 3.30 3.62 rs1029754 0.84 1.51 3.62 0.23 0.12rs17808998 0.56 1.35 3.30 1.57 0.81 rs9895463 0.58 1.00 3.23 1.23 2.04rs11868422 0.14 1.71 3.05 2.06 1.85 rs1877823 0.73 1.26 3.03 3.22 3.52

TABLE 23 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs8065080 TRPV1 Exon11 (NM_080706.1), 17 3,427,196 3.67 0.69 TRPV1Exon12 (NM_080705.1), TRPV1 Exon12 (NM_018727.3), TRPV1 Exon13(NM_080704.1) rs8082149 LOC342600 Intron2 (XM_292624) 17 51,927,894 3.520.92 rs2269459 POLR2A Intron22 (NM_000937.2) 17 7,353,762 3.11 0.79rs2072255 KIAA0672 Intron10 (XM_375408) 17 12,793,117 3.09 0.21rs9788983 RPH3AL Intron6 (NM_006987.2) 17 129,457 3.05 0.89 rs1879610LOC441825 +255198bp (XM_497596) 18 73,469,750 1.98 0.95 rs11876045LOC441816 −222690bp (XM_497584) 18 20,564,102 3.73 0.28 rs17070861 BCL2Intron1 (NM_000633.1), 18 59,057,460 0.72 0.94 BCL2 +78655bp(NM_000657.1) rs1790870 CYB5 +163bp (NM_001914.1), 18 70,071,349 3.860.86 CYB5 +163bp (NM_148923.1) rs1790858 CYB5 Intron3 (NM_001914.1), 1870,075,799 3.74 0.86 CYB5 Intron3 (NM_148923.1) rs17187933 LOC441816−214621bp (XM_497584) 18 20,556,033 3.55 0.26 rs17088997 CYB5 +3361bp(NM_001914.1), 18 70,068,151 3.62 0.86 CYB5 +3361bp (NM_148923.1)rs1372481 LOC390856 Intron1 (XM_497590) 18 49,466,756 3.51 0.96rs10468763 CLUL1 Intron5 (NM_014410.4), 18 622,239 0.40 0.22 CLUL1Intron5 (NM_199167.1) rs3862680 DCC Intron1 (NM_005215.1) 18 48,184,3383.65 0.60 rs3910695 LOC390856 Intron1 (XM_497590) 18 49,464,638 3.350.96 rs3862681 DCC Intron1 (NM_005215.1) 18 48,184,688 3.53 0.60rs7238490 METTL4 +571947bp (NM_022840.2) 18 1,955,583 3.40 0.71rs9951036 LOC390856 Intron1 (XM_497590) 18 49,515,735 3.18 0.96High-Risk Allele Frequency in Critical rate, Odds Ratio Odds RatioNon-Patient Odds Ratio Genotype (Homozygote) (Heterozygote) dbSNP IDGroup (Formula 3) (−logP) (Formula 4) (Formula 5) rs8065080 0.60 1.512.88 2.25 1.51 rs8082149 0.86 1.85 2.66 3.49 1.99 rs2269459 0.72 1.522.51 2.46 1.63 rs2072255 0.14 1.63 2.43 3.35 1.53 rs9788983 0.82 1.652.40 3.21 2.00 rs1879610 0.91 1.72 3.48 0.26 0.11 rs11876045 0.20 1.613.41 1.79 1.88 rs17070861 0.93 1.33 3.34 ND ND rs1790870 0.78 1.70 3.301.99 1.06 rs1790858 0.78 1.68 3.18 1.99 1.08 rs17187933 0.18 1.62 3.111.86 1.81 rs17088997 0.78 1.67 3.07 1.95 1.06 rs1372481 0.92 2.35 3.071.52 0.58 rs10468763 0.21 1.12 3.06 0.50 1.61 rs3862680 0.50 1.49 2.972.24 1.56 rs3910695 0.92 2.28 2.90 1.53 0.60 rs3862681 0.50 1.48 2.842.19 1.54 rs7238490 0.62 1.49 2.72 2.04 1.27 rs9951036 0.92 2.23 2.721.52 0.62

TABLE 24 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs339858 LOC441816 −124776bp (XM_497584) 18 20,466,188 3.14 0.16rs11151937 CYB5 +4859bp (NM_001914.1), 18 70,066,653 3.06 0.53 CYB5+4859bp (NM_148923.1) rs8094863 LOC390855 Intron3 (XM_497589) 1847,458,218 3.17 0.50 rs17260163 LOC441816 −250775bp (XM_497584) 1820,592,187 3.13 0.29 rs8086430 LOC147468 +250079bp (XM_091809) 1820,600,317 3.10 0.29 rs16940484 C18orf17 Intron6 (NM_153211.1) 1819,936,298 3.09 0.34 rs7229080 LOC390856 Intron1 (XM_497590) 1849,503,583 3.19 0.97 rs10502927 LOC390855 Intron3 (XM_497589) 1847,502,071 3.01 0.49 rs17660384 ZNF175 −10715bp (NM_007147.2) 1956,755,628 3.53 0.21 rs2864107 ZNF175 −5504bp (NM_007147.2) 1956,760,839 3.40 0.21 rs1433083 FLJ12644 Exon5 (NM_023074.2) 1957,085,796 3.14 0.95 rs6097745 BCAS1 Intron3 (NM_003657.1) 20 52,101,5331.67 0.29 rs2870304 BCAS1 Intron3 (NM_003657.1) 20 52,106,624 1.74 0.30rs8123014 C20orf23 +571310bp (NM_024704.3) 20 15,629,440 2.16 0.75rs6115865 C20orf194 −37687bp (XM_045421) 20 3,307,303 3.63 0.38rs7268851 C20orf17 Intron2 (NM_173485.2) 20 51,501,200 3.45 0.73rs6134494 LOC440753 +240718bp (XM_498845) 20 12,196,345 3.12 0.22rs3817879 PLCB1 Intron3 (NM_015192.2), 20 8,470,921 3.17 0.80 PLCB1Intron3 (NM_182734.1) rs2743246 MATN4 Intron5 (NM_003833.2), 2043,362,112 3.10 0.88 MATN4 Intron4 (NM_030590.1), MATN4 Intron3(NM_030592.1) rs6014430 KIAA1755 Intron2 (XM_028810) 20 36,305,948 3.050.11 rs2154450 RUNX1 Intron5 (NM_001754.2) 21 35,141,436 0.85 0.44rs4817695 RUNX1 Intron5 (NM_001754.2) 21 35,141,187 0.66 0.44 rs2825423LOC388817 +373452bp (XM_371409) 21 19,526,124 3.31 0.26 High-Risk AlleleFrequency in Critical rate, Odds Ratio Odds Ratio Non-Patient Odds RatioGenotype (Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP)(Formula 4) (Formula 5) rs339858 0.10 1.75 2.70 1.95 1.90 rs111519370.44 1.43 2.68 2.01 1.68 rs8094863 0.41 1.44 2.55 2.12 1.32 rs172601630.21 1.53 2.54 2.21 1.59 rs8086430 0.21 1.52 2.51 2.20 1.58 rs169404840.26 1.49 2.51 2.02 1.58 rs7229080 0.93 2.28 2.49 3.03 1.30 rs105029270.41 1.43 2.45 2.09 1.27 rs17660384 0.14 1.69 3.02 5.12 1.57 rs28641070.14 1.68 2.90 4.82 1.58 rs1433083 0.91 2.07 2.66 ND ND rs6097745 0.241.33 3.56 1.00 1.92 rs2870304 0.25 1.33 3.49 1.06 1.91 rs8123014 0.681.38 3.20 1.23 0.66 rs6115865 0.29 1.52 2.87 2.29 1.52 rs7268851 0.651.51 2.86 2.08 1.27 rs6134494 0.15 1.61 2.86 1.59 1.86 rs3817879 0.721.54 2.52 2.65 1.89 rs2743246 0.81 1.64 2.43 2.97 1.85 rs6014430 0.061.94 2.03 3.66 1.69 rs2154450 0.40 1.18 3.94 1.14 2.01 rs4817695 0.411.14 3.69 1.10 1.94 rs2825423 0.19 1.58 2.64 3.09 1.38

TABLE 25 High-Risk Allele Critical rate, Frequency in Physical AlleleGlaucoma Patient dbSNP ID Exon, Intron Chromosome Location (−logP) Grouprs4823324 E46L Intron10 (NM_013236.1) 22 44,558,660 3.69 0.51 rs2857648NF2 Intron10 (NM_181825.1), 22 28,391,122 3.02 0.73 NF2 Intron8(NM_181831.1), NF2 Intron10 (NM_000268.2), NF2 Intron10 (NM_016418.4),NF2 Intron11 (NM_181826.1), NF2 Intron10 (NM_181827.1), NF2 Intron9(NM_181828.1), NF2 Intron9 (NM_181829.1), NF2 Intron8 (NM_181830.1), NF2Intron10 (NM_181832.1), NF2 Intron4 (NM_181833.1), NF2 Intron5(NM_181834.1), NF2 Intron8 (NM 181835.1) rs6006787 FBLN1 +65094bp(NM_006487.2), 22 44,340,222 3.31 0.50 FBLN1 +60443bp (NM_001996.2),FBLN1 +58104bp (NM_006485.2), FBLN1 +22671bp (NM_006486.2) rs572159LOC284898 −273642bp (XM_379044) 22 26,054,663 3.11 0.94 rs467812C22orf19 Intron2 (NM_003678.3) 22 28,265,503 3.22 0.27 rs5765558 E46L−24767bp (NM_013236.1) 22 44,363,516 3.05 0.58 rs6006179 C22orf19Intron19 (NM_003678.3) 22 28,231,255 3.03 0.27 High-Risk AlleleFrequency in Critical rate, Odds Ratio Odds Ratio Non-Patient Odds RatioGenotype (Homozygote) (Heterozygote) dbSNP ID Group (Formula 3) (−logP)(Formula 4) (Formula 5) rs4823324 0.41 1.49 3.04 2.26 1.32 rs28576480.65 1.46 2.79 1.67 0.95 rs6006787 0.40 1.46 2.72 2.22 1.38 rs5721590.89 1.92 2.48 4.67 2.44 rs467812 0.19 1.56 2.48 2.23 1.57 rs57655580.49 1.43 2.34 2.01 1.37 rs6006179 0.20 1.53 2.33 2.19 1.55

Tables 5 to 25 list dbSNP ID number or Affimetrix Array ID number forspecifying known single nucleotide polymorphisms obtained, the exon,intron information (in a case where a single nucleotide polymorphismexists on a gene, the gene name and the exon or intron in which SNPexists are shown, and in a case where a single nucleotide polymorphismdoes not exist on a gene, neighboring genes and a distance between thegene and the single nucleotide polymorphism are shown), the chromosomenumber at which the single nucleotide polymorphism exists, the physicallocation of the single nucleotide polymorphism, the p-value for anallele according to a chi-square test (−log P), the high-risk allelefrequencies in the glaucoma patient group and the non-patient group, theodds ratio for an allele, the p-value for a genotype according to achi-square test (−log P), the odds ratio for a genotype of a homozygote,and the odds ratio for a genotype of a heterozygote. Here, in thetables, a portion of which odds ratio is indicated as ND shows a casewhere any one of the number of detection in the denominator is 0, sothat the odds ratio could not be calculated.

According to the above studies, 413 single nucleotide polymorphisms ofwhich alleles or genotypes were associated with glaucoma at a p-value of1×10⁻³ or less were found.

When the allele or genotype frequencies listed in Tables 5 to 25 werecompared between the non-patients without having family history and theglaucoma patients, a statistical difference was found. By determining anallele of any one of these single nucleotide polymorphisms, whether ornot an allele that is identified in a higher frequency in the glaucomapatient group than that of the non-patient group exists in the samplecan be determined.

Example 4 Comparison of Single Nucleotide Polymorphisms BetweenProgressive Glaucoma Cases and Nonprogressive Glaucoma Cases

The comparison on single nucleotide polymorphisms was made forprogressive glaucoma cases and nonprogressive glaucoma cases in the samemanner as in Example 3.

Concretely, blood donated under the consent on free will of theparticipants after having sufficiently explained the contents of studiesfrom 210 cases of patients with progressive visual loss within a giventime period, despite the treatments for lowering an intraocular pressuresuch as a drug for lowering an intraocular pressure or a surgicaloperation (progressive glaucoma cases), and 175 cases of patientswithout the progression (nonprogressive glaucoma cases), among theprimary open-angle glaucoma patients and the normal tension glaucomapatients diagnosed on the basis of Guidelines offered by Japan GlaucomaSociety, was used as a specimen, and alleles frequencies and genotypesfrequencies between the groups were also compared by performing theanalysis in the same manner as in Example 3. Alleles frequencies andgenotype frequencies were statistically compared according to thechi-square test in the same manner. Single nucleotide polymorphisms ofwhich alleles or genotypes show association with the progression ofglaucoma at a p-value of 1×10⁻⁴ or less, i.e. −log P of 4 or more arelisted in Tables 26 to 28. Here, the odds ratio for association of anallele with the progression of glaucoma, and the odds ratio forassociation of a genotype with the progression of glaucoma in each ofthe tables, respectively were calculated on the basis of the followingformulas (6) to (8).

Odds Ratio for Allele=[(Number of Detection of an Allele Identified inHigh Frequency in Progressive Glaucoma Group, in Progressive GlaucomaGroup)/(Number of Detection of an Allele Opposite to the AlleleIdentified in High Frequency in Progressive Glaucoma Group, inProgressive Glaucoma Group)]/[(Number of Detection of the AlleleIdentified in High Frequency in Progressive Glaucoma Group, inNonprogressive Glaucoma Group)/(Number of Detection of the AlleleOpposite to the Allele Identified in High Frequency in ProgressiveGlaucoma Group, in Nonprogressive Glaucoma Group)]  formula (6)

Odds Ratio for Genotype of Homozygote=[(Number of Detection of aGenotype Having Homozygote of an Allele Identified in High Frequency inProgressive Glaucoma Group, in Progressive Glaucoma Group)/(Number ofDetection of a Genotypes Having Homozygote of an Allele Identified inHigh Frequency in Nonprogressive Glaucoma Group, in Progressive GlaucomaGroup)]/[(Number of Detection of the Genotype Having Homozygote of theAllele Identified in High Frequency in Progressive Glaucoma Group, inNonprogressive Glaucoma Group)/(Number of Detection of the GenotypeHaving Homozygote of the Allele Identified in High Frequency inNonprogressive Glaucoma Group, in Nonprogressive GlaucomaGroup)]  formula (7)

Odds Ratio for Genotype of Heterozygote=[(Number of Detection of aGenotype of Heterozygote in Progressive Glaucoma Group)/(Number ofDetection of a Genotype Having Homozygote of an Allele Identified inHigh Frequency in Nonprogressive Glaucoma Group, in Progressive GlaucomaGroup)]/[(Number of Detection of the Genotype of Heterozygote inNonprogressive Glaucoma Group)/(Number of Detection of the GenotypeHaving Homozygote of the Allele Identified in High Frequency inNonprogressive Glaucoma Group, in Nonprogressive GlaucomaGroup)]  formula (8)

TABLE 26 High-Risk High-Risk Allele Critical rate, Allele Frequency inAllele Frequency in 1/ Physical Allele Progressive Nonprogressive dbSNPID Allele 2 Exon, Intron Chromosome Location (−logP) Glaucoma GroupGlaucoma Group rs11211059 A/G EIF2B3 Intron4 (NM_020365.1) 1 45,099,3110.28 0.77 0.75 rs4927088 C/T SSBP3 Intron4 (NM_145716.1), 1 54.487,2241.10 0.60 054 SSBP3 Intron4 (NM_018070.2) rs10172264 G/T LOC402072+152420bp (XM_377741) 2 53,313,788 4.32 0.20 0.09 rs10460373 G/T UBE2E3−372131bp (NM_182678.1), 2 181,298,487 3.24 0.82 0.72 UBE2E3 −372361bp(NM_006357.2) rs1520855 C/T FLJ12519 −24239bp (NM_032168.1) 2190,107,426 1.13 0.65 0.59 rs1827101 C/T ITPR1 +23266p (NM_002222.1) 34,866,407 1.36 0.75 0.69 rs4635691 C/G ITPR1 +2783bp (NM_002222.1) 34,866,864 1.24 0.75 0.69 rs9819062 A/C ITPR1 +14847bp (NM_002222.1) 34,878,928 1.41 0.75 0.68 rs12638937 G/T ITPR1 +15316bp (NM_002222.1) 34,879,397 1.32 0.75 0.69 rs3805345 A/G PAPSS1 Intron5 (NM_005443.4) 4108,943,706 3.56 0.65 0.52 rs3805347 C/T PAPSS1 Intron5 (NM_005443.4) 4108,959,666 3.70 0.67 0.53 rs17066530 A/G LOC285501 +636489bp(XM_209640) 4 179,923,545 4.60 0.92 0.81 rs405806 A/C LOC441062+175809bp (XM_498994) 5 18,167,512 4.03 0.55 0.41 rs401889 A/G LOC441062+175873bp (XM_498994) 5 18,167,576 4.60 0.53 0.38 rs4308461 A/C SV2C−75087bp (XM_043493) 5 75,339,908 4.03 0.79 0.66 rs2547455 C/T SV2C−33137bp (XM_043493) 5 75,381,858 4.40 0.80 0.67 rs2042974 C/G LHFPL2−11058bp (NM_005779.1) 5 77,852,925 1.24 0.86 0.81 rs7719483 A/C LHFPL2−19056bp (NM_005779.1) 5 77,860,923 0.88 0.86 0.82 rs17215893 C/T LHFPL2−20235bp (NM_005779.1) 5 77,862,102 0.85 0.86 0.82 rs10045987 C/T LHFPL2−31149bp (NM_005779.1) 5 77,873,016 0.88 0.86 0.82 rs11949567 A/G LHFPL2−35281bp (NM_005779.1) 5 77,877,148 0.88 0.86 0.82 rs11950379 A/G LHFPL2−35775bp (NM_005779.1) 5 77,877,642 0.79 0.85 0.82 rs6860516 A/G LHFPL2−35961bp (NM_005779.1) 5 77,877,828 0.88 0.86 0.82 rs6881598 A/G LHFPL2−37710bp (NM_005779.1) 5 77,879,577 0.88 0.86 0.82 Critical rate, OddsRatio Odds Ratio Sequence Sequence High Risk Odds Ratio Genotype(Homozygote1) (Heterozygote) Containing Containing dbSNP ID Allele(Formula 6) (−logP) (Formula 7) (Formula 8) Allele 1 Allele 2 rs11211059Allele 2 1.12 4.51 9.28 15.68 SEQ ID No: 81 SEQ ID No: 82 rs4927088Allele 1 1.29 4.56 2.12 3.61 SEQ ID No: 83 SEQ ID No: 84 rs10172264Allele 1 2.43 3.91 2.54 2.85 SEQ ID No: 85 SEQ ID No: 86 rs10460373Allele 1 1.81 4.16 1.42 0.54 SEQ ID No: 87 SEQ ID No: 88 rs1520855Allele 1 1.31 4.67 2.51 4.22 SEQ ID No: 89 SEQ ID No: 90 rs1827101Allele 2 1.39 4.66 0.73 0.29 SEQ ID No: 91 SEQ ID No: 92 rs4635691Allele 1 1.36 4.25 0.76 0.31 SEQ ID No: 93 SEQ ID No: 94 rs9819062Allele 1 1.39 4.23 0.81 0.33 SEQ ID No: 95 SEQ ID No: 96 rs12638937Allele 1 1.38 4.03 0.80 0.33 SEQ ID No: 97 SEQ ID No: 98 rs3805345Allele 2 1.73 4.10 2.57 0.94 SEQ ID No: 99 SEQ ID No: 100 rs3805347Allele 2 1.77 4.07 2.92 1.09 SEQ ID No: 101 SEQ ID No: 102 rs17066530Allele 1 2.62 4.15 4.56 1.55 SEQ ID No: 103 SEQ ID No: 104 rs405806Allele 2 1.77 3.38 2.95 2.11 SEQ ID No: 105 SEQ ID No: 106 rs401889Allele 2 1.86 4.14 3.23 2.37 SEQ ID No: 107 SEQ ID No: 108 rs4308461Allele 1 1.89 3.12 3.36 1.81 SEQ ID No: 109 SEQ ID No: 110 rs2547455Allele 1 1.97 3.63 3.03 1.39 SEQ ID No: 111 SEQ ID No: 112 rs2042974Allele 2 1.47 4.37 ND ND SEQ ID No: 113 SEQ ID No: 114 rs7719483 Allele2 1.34 5.18 ND ND SEQ ID No: 115 SEQ ID No: 116 rs17215893 Allele 1 1.345.14 ND ND SEQ ID No: 117 SEQ ID No: 118 rs10045987 Allele 2 1.34 5.18ND ND SEQ ID No: 119 SEQ ID No: 120 rs11949567 Allele 2 1.34 5.18 ND NDSEQ ID No: 121 SEQ ID No: 122 rs11950379 Allele 2 1.31 4.97 ND ND SEQ IDNo: 123 SEQ ID No: 124 rs6860516 Allele 1 1.34 5.18 ND ND SEQ ID No: 125SEQ ID No: 126 rs6881598 Allele 2 1.34 5.18 ND ND SEQ ID No: 127 SEQ IDNo: 128

TABLE 27 High-Risk High-Risk Allele Critical rate, Allele Frequency inAllele Frequency in 1/ Physical Allele Progressive Nonprogressive dbSNPID Allele 2 Exon, Intron Chromosome Location (−logP) Glaucoma GroupGlaucoma Group rs6886783 C/T LHFPL2 −37765bp (NM_005779.1) 5 77,879,6320.88 0.86 0.82 rs6877525 C/T LHFPL2 −38871bp (NM_005779.1) 5 77,880,7380.88 0.86 0.82 rs12697888 C/T LHFPL2 −13535bp (NM_005779.1) 5 77,895,4020.88 0.86 0.82 rs1978629 C/T LHFPL2 −56045bp (NM_005779.1) 5 77,897,9120.88 0.86 0.82 rs10076149 C/G LHFPL2 −68743bp (NM_005779.1) 5 77,910,6100.88 0.86 0.82 rs730781 C/T LHFPL2 −84106bp (NM_005779.1) 5 77,925,9730.85 0.86 0.82 rs9461154 C/T LRRC16 −112934bp (NM_017640.2) 6 25,506,0141.41 0.32 0.25 rs13193932 C/G ARHGAP18 Intron1 (NM_033515.2) 6130,008,475 1.70 0.83 0.76 rs17070863 A/G LOC441173 +172209bp(XM_496827) 6 141,772,290 4.46 0.55 0.40 rs1877885 C/G LOC340268 Intron1(XM_294634) 7 9,625,295 4.29 0.60 0.45 rs1913603 A/C LOC340268 Intron1(XM_294634) 7 9,664,816 4.03 0.64 0.49 rs10230371 A/G HDAC9 Intron21(NM_058176.1), 7 18,668,137 1.05 0.41 0.35 HDAC9 Intron21 (NM_178423.1),HDAC9 Intron19 (NM_178425.1), HDAC9 +186432bp (NM_014707.1), HDAC9+19625bp (NM 058177.1) rs17152739 A/G LOC401384 +201741bp (XM_379506) 778,935,541 4.66 0.78 0.64 rs4316157 C/T LOC340357 Intron3 (XM_499106) 812,677,322 4.65 0.48 0.33 rs10503907 A/G NRG1 −233743bp (NM_013958.1), 832,291,552 4.11 0.92 0.83 NRG1 −233775bp (NM_013957.1), NRG1 −233799bp(NM_004495.1), NRG1 −233842bp (NM_013961.1), NRG1 −254103bp(NM_013964.1), NRG1 −234127bp (NM_013960.1), NRG1 −234143bp(NM_013956.1), NRG1 −281336bp (NM_013962.1), NRG1 −332731bp(NM_013959.1) Critical rate, Odds Ratio Odds Ratio Sequence SequenceHigh Risk Odds Ratio Genotype (Homozygote1) (Heterozygote) ContainingContaining dbSNP ID Allele (Formula 6) (−logP) (Formula 7) (Formula 8)Allele 1 Allele 2 rs6886783 Allele 1 1.34 5.18 ND ND SEQ ID No: 129 SEQID No: 130 rs6877525 Allele 2 1.34 5.18 ND ND SEQ ID No: 131 SEQ ID No:132 rs12697888 Allele 1 1.34 5.18 ND ND SEQ ID No: 133 SEQ ID No: 134rs1978629 Allele 2 1.34 5.18 ND ND SEQ ID No: 135 SEQ ID No: 136rs10076149 Allele 2 1.34 5.18 ND ND SEQ ID No: 137 SEQ ID No: 138rs730781 Allele 1 1.34 5.09 ND ND SEQ ID No: 139 SEQ ID No: 140rs9461154 Allele 2 1.39 4.01 11.34 0.85 SEQ ID No: 141 SEQ ID No: 142rs13193932 Allele 2 1.52 4.30 22.83 26.08 SEQ ID No: 143 SEQ ID No: 144rs17070863 Allele 2 1.86 3.61 3.42 1.72 SEQ ID No: 145 SEQ ID No: 146rs1877885 Allele 2 1.80 3.67 3.45 2.04 SEQ ID No: 147 SEQ ID No: 148rs1913603 Allele 2 1.79 3.75 3.85 2.37 SEQ ID No: 149 SEQ ID No: 150rs10230371 Allele 1 1.29 4.38 1.11 2.63 SEQ ID No: 151 SEQ ID No: 152rs17152739 Allele 2 1.98 3.78 3.43 1.65 SEQ ID No: 153 SEQ ID No: 154rs4316157 Allele 2 1.89 3.65 3.29 1.88 SEQ ID No. 155 SEQ ID No: 156rs10503907 Allele 1 2.46 3.27 8.80 3.83 SEQ ID No: 157 SEQ ID No: 158

TABLE 28 High-Risk Allele High-Risk Allele Allele Critical rate,Frequency in Frequency in 1/ Physical Allele Progressive NonprogressivedbSNP ID Allele 2 Exon, Intron Chromosome Location (−logP) GlaucomaGroup Glaucoma Group rs9650336 C/T LOC286140 −47376bp (XM_209913) 838,625,315 4.11 0.67 0.53 rs1541082 A/C PIP5K1B Intron15 (NM_003358.1) 968,851,654 4.05 0.37 0.24 rs4979255 C/T LOC442430 −50518bp (XM_498339) 9107,542,392 1.50 0.69 0.61 rs2395453 C/G KCNMA1 Intron18 (NM_002247.2)10 78,411,565 1.77 0.60 0.51 rs2131216 A/T KCNMA1 Intron18 (NM_002247.2)10 78,426,609 1.67 0.59 0.51 rs7112492 A/C LDHA −10601bp (NM_005566.1)11 18,362,086 3.70 0.38 0.26 rs4755605 C/T LOC387761 −170163bp(XM_373495) 11 42,404,449 3.08 0.57 0.45 rs10892454 A/C LOC440070+32494bp (XM_498530) 11 119,148,037 0.09 0.47 0.47 rs4269933 C/TLOC440070 +38035bp (XM_498530) 11 119,153,578 0.08 0.47 0.47 rs2322728A/G FLJ40224 +258937bp (NM_173579.1) 11 126,640,100 0.04 0.28 0.28rs4350423 A/G FLJ40126 Intron18 (NM_173599.1), 12 38,515,235 4.28 0.240.13 SLC2A13 Intron6 (NM_052885.1) rs10784314 C/T PPM1H Intron4(XM_350880) 12 61,442,746 1.93 0.85 0.78 rs4408378 A/G LOC401725+252078bp (XM_377278) 12 82,300,515 4.01 0.82 0.70 rs11059862 A/GDKFZp761O2018 +33295bp (XM_044062) 12 127,750,629 4.11 0.94 0.85rs17184839 A/G LOC440142 +13577bp (XM_495960) 13 59,763,528 4.07 0.140.05 rs7212115 G/T LOC400573 −182083bp (XM_378649) 17 10,832,202 4.050.88 0.78 rs295869 C/T LOC388375 +71591bp (XM_373726) 17 32,221,458 2.760.44 0.33 rs6045676 C/G PDYN +18232bp (NM_024411.2) 20 1,889,171 4.110.35 0.22 rs909882 A/G CHD6 Intron24 (NM_032221.3) 20 39,509,923 4.370.81 0.68 rs6017164 C/T C20orf65 −26539bp (NM_176791.2) 20 41,815,5204.15 0.55 0.40 rs7275647 A/G NCAM2 Intron5 (NM_004540.2) 21 21,586,9124.62 0.69 0.55 rs2837255 A/C PCP4 −17259bp (NM_006198.1) 21 40,143,9914.33 0.70 0.56 Critical rate, Odds Ratio Odds Ratio Sequence SequenceHigh Risk Odds Ratio Genotype (Homozygote1) (Heterozygote) ContainingContaining dbSNP ID Allele (Formula 6) (−logP) (Formula 7) (Formula 8)Allele 1 Allele 2 rs9650336 Allele 1 1.80 4.06 2.58 1.02 SEQ ID No: 159SEQ ID No: 160 rs1541082 Allele 1 1.87 3.54 4.89 1.65 SEQ ID No: 161 SEQID No: 162 rs4979255 Allele 1 1.39 4.03 1.16 0.46 SEQ ID No: 163 SEQ IDNo: 164 rs2395453 Allele 1 1.42 4.73 1.68 0.55 SEQ ID No: 165 SEQ ID No:166 rs2131216 Allele 2 1.40 4.14 1.72 0.59 SEQ ID No: 167 SEQ ID No: 168rs7112492 Allele 2 1.80 4.03 2.25 2.50 SEQ ID No: 169 SEQ ID No: 170rs4755605 Allele 1 1.63 4.13 3.34 3.05 SEQ ID No: 171 SEQ ID No: 172rs10892454 Allele 1 1.03 4.12 1.29 0.45 SEQ ID No: 173 SEQ ID No: 174rs4269933 Allele 2 1.03 4.20 1.29 0.44 SEQ ID No: 175 SEQ ID No: 176rs2322728 Allele 2 1.02 4.00 3.53 0.55 SEQ ID No: 177 SEQ ID No: 178rs4350423 Allele 2 2.20 3.41 8.59 1.82 SEQ ID No: 179 SEQ ID No: 180rs10784314 Allele 1 1.62 5.56 ND ND SEQ ID No: 181 SEQ ID No: 182rs4408378 Allele 1 1.97 3.22 3.63 1.81 SEQ ID No: 183 SEQ ID No: 184rs11059862 Allele 1 2.61 3.33 5.98 2.27 SEQ ID No: 185 SEQ ID No: 186rs17184839 Allele 1 2.98 3.54 ND 3.09 SEQ ID No: 187 SEQ ID No: 188rs7212115 Allele 2 2.17 2.12 2.65 1.55 SEQ ID No: 189 SEQ ID No: 190rs295869 Allele 1 1.60 4.93 1.80 3.00 SEQ ID No: 191 SEQ ID No: 192rs6045676 Allele 2 1.91 3.66 2.90 2.23 SEQ ID No: 193 SEQ ID No: 194rs909882 Allele 1 2.01 3.58 4.37 2.25 SEQ ID No: 195 SEQ ID No: 196rs6017164 Allele 2 1.80 3.44 3.33 1.62 SEQ ID No: 197 SEQ ID No: 198rs7275647 Allele 1 1.89 3.98 3.18 1.43 SEQ ID No: 199 SEQ ID No: 200rs2837255 Allele 1 1.86 3.37 3.28 1.82 SEQ ID No: 201 SEQ ID No: 202

Tables 26 to 28 list dbSNP ID number or Affimetrix Array ID numberspecifying known single nucleotide polymorphisms obtained, each of basesconstituting Allele 1 and Allele 2, the exon, intron information (in acase where a single nucleotide polymorphism exists on a gene, the genename and the exon or intron in which SNP exists are shown, and in a casewhere a single nucleotide polymorphism does not exist on a gene,neighboring genes and a distance between the gene and the singlenucleotide polymorphism are shown), the chromosome number at which thesingle nucleotide polymorphism exists, the physical location of thesingle nucleotide polymorphism, the p-value for an allele according to achi-square test (−log P), the high-risk allele frequencies in theprogressive glaucoma group and the nonprogressive glaucoma group, thetype of the high-risk allele (indicating whether the high-risk allele isAllele 1 or Allele 2), the odds ratio for an allele, the p-value forgenotype according to a chi-square test (−log P), the odds ratio for agenotype of a homozygote, the odds ratio for a genotype of aheterozygote, and SEQ ID NO of the sequence containing Allele 1 and SEQID NO of the sequence containing Allele 2 in each of the polymorphicsites. Here, in the tables, a portion of which odds ratio is indicatedas ND shows a case where any one of the number of detection in thedenominator is 0, so that the odds ratio could not be calculated.

According to the above studies, 61 single nucleotide polymorphisms ofwhich alleles or genotypes were associated with the progression ofglaucoma at a p-value of 1×10⁻⁴ or less were found.

When the allele or genotype frequencies listed in Tables 26 to 28 werecompared between the progressive glaucoma cases and the nonprogressiveglaucoma cases, a statistical difference was found. By determining anallele of any one of these single nucleotide polymorphisms, whether ornot an allele that is identified in a higher frequency in theprogressive glaucoma group than that of the nonprogressive glaucomagroup exists in the sample can be determined.

The allele or genotype identified in a high frequency in the progressiveglaucoma group for a single nucleotide polymorphism listed in Tables 26to 28 can be used as a marker showing that a progressive risk ofglaucoma is high. On the other hand, an allele that is opposite to theallele or a genotype other than the genotype can be used as a markershowing that a progressive risk of glaucoma is low.

Also, a single nucleotide polymorphism of which allele or genotype showsassociation with the progression of glaucoma at a p-value of 1×10⁻³ orless, i.e. −log P of 3 or more, is listed in Tables 29 to 51.

TABLE 29 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs1920146 FMO3 −14117bp (NM_006894.3) 1 167,777,607 3.00 0.16rs594105 C8A Intron4 (NM_000562.1) 1 57,055,277 0.82 0.65 rs490647 GRIK3+23871bp (NM_000831.2) 1 36,911,836 3.13 0.39 rs10489624 C8A Intron6(NM_000562.1) 1 57,061,635 0.83 0.65 rs11117962 LOC128153 +9779bp(NM_138796.2) 1 214,438,658 1.33 0.60 rs868162 NPHP4 Intron22(NM_015102.2) 1 5,868,502 0.74 0.76 rs525798 GRIK3 +25728bp(NM_000831.2) 1 36,909,979 3.12 0.40 rs11120300 SMYD2 Intron11(NM_020197.1) 1 210,897,894 1.38 0.08 rs10494300 KCNN3 Intron3(NM_170782.1), 1 151,539,619 3.13 0.61 KCNN3 Intron3 (NM_002249.3)rs17401966 KIF1B Intron24 (NM_015074.2), 1 10,319,737 2.53 0.28 KIF1B+18633bp (NM_183416.2) rs687328 GADD45A −40088bp (NM_001924.2) 167,822,816 3.19 0.75 rs7517439 EIF2B3 +3647bp (NM_020365.1) 1 44,981,9600.01 0.75 rs479714 GRIK3 +26576bp (NM_000831.2) 1 36,909,131 2.84 0.39rs7528341 GRIK3 +125440bp (NM_000831.2) 1 36,810,267 3.27 0.75 rs1339411KCNK2 +61589bp (NM_014217.1) 1 211,859,142 3.20 0.33 rs947130 LOC391075−11088bp (XM_497702) 1 119,728,774 3.47 0.82 rs7534078 SYT2 Intron1(NM_177402.3) 1 199,346,710 3.84 0.37 rs479779 GRIK3 +10551bp(NM_000831.2) 1 36,925,156 3.03 0.39 rs2993076 GRIK3 +5529bp(NM_000831.2) 1 36,930,178 3.00 0.36 rs11590929 LMO4 +403174bp(NM_006769.2) 1 87,926,458 3.65 0.96 rs1416658 KCNX2 +6613bp(NM_014217.1) 1 211,804,166 3.28 0.32 rs4652921 GRIK3 +91841bp(NM_000831.2) 1 36,843,866 3.22 0.66 rs10157596 SLC35F3 −17535bp(NM_173508.1) 1 230,329,879 3.29 0.71 rs1416659 KCNK2 +6647bp(NM_014217.1) 1 211,804,200 3.17 0.31 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype(Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP)(Formula 7) (Formula 8) rs1920146 0.08 2.14 3.79 0.78 3.05 rs594105 0.601.24 3.74 0.95 0.41 rs490647 0.28 1.69 3.43 1.92 2.39 rs10489624 0.601.24 3.39 1.00 0.44 rs11117962 0.53 1.34 3.32 1.49 0.60 rs868162 0.721.25 3.32 0.41 0.21 rs525798 0.28 1.68 3.28 1.97 2.33 rs11120300 0.041.90 3.14 0.23 4.08 rs10494300 0.49 1.64 3.14 2.56 1.09 rs17401966 0.191.68 3.09 17.83 1.28 rs687328 0.63 1.71 3.07 3.66 3.07 rs7517439 0.751.01 3.05 4.99 7.80 rs479714 0.28 1.64 3.01 1.86 2.26 rs7528341 0.631.73 2.97 2.40 1.14 rs1339411 0.22 1.76 2.91 2.53 2.08 rs947130 0.711.86 2.89 4.69 2.75 rs7534078 0.25 1.84 2.89 2.83 1.87 rs479779 0.281.67 2.86 2.00 2.16 rs2993076 0.25 1.69 2.84 2.00 2.15 rs11590929 0.892.98 2.83 4.15 1.35 rs1416658 0.21 1.79 2.82 2.63 2.02 rs4652921 0.541.67 2.81 2.56 1.25 rs10157596 0.59 1.71 2.80 3.48 2.28 rs1416659 0.211.77 2.79 2.48 2.04

TABLE 30 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs11120527 KCNK2 Intron6 (NM_014217.1) 1 211,796,452 3.16 0.32rs10494994 KCNK2 Intron5 (NM_014217.1) 1 211,750,602 3.50 0.26 rs6665581VAMP4 −9932bp (NM_201994.1), 1 168,452,803 3.09 0.39 VAMP4 −9932bp(NM_003762.2) rs12120152 VAMP4 −12595bp (NM_201994.1), 1 168,455,4663.09 0.39 VAMP4 −12595bp (NM_003762.2) rs2293325 CD3Z Intron1(NM_000734.2), 1 164,157,804 3.18 0.78 CD3Z Intron1 (NM_198053.1)rs6577539 CA6 −16705bp (NM_001215.1) 1 8,923,501 3.16 0.94 rs34305923GRIK3 +122474bp (NM_000831.2) 1 36,813,233 3.10 0.74 rs1315219 FLJ23129Intron7 (NM_024763.3), 1 67,031,546 3.32 0.58 FLJ23129 Intron7(NM_207014.1) rs10798603 VAMP4 Intron4 (NM_201994.1), 1 168,412,039 3.370.36 VAMP4 Intron4 (NM_003762.2) rs1317252 TDE2L Intron2 (NM_178865.2) 131,566,351 3.25 0.91 rs12024194 VAMP4 −12277bp (NM_201994.1), 1168,455,148 3.21 0.22 VAMP4 −12277bp (NM_003762.2) rs10489250 VAMP4−4860bp (NM_201994.1), 1 168,447,731 3.03 0.22 VAMP4 −4860bp(NM_003762.2) rs271351 LOC391025 −173869bp (XM_372775) 1 29,821,213 3.210.16 rs6689380 LOC339535 −409013bp (XM_378941) 1 235,384,371 3.08 0.97rs9943293 VAMP4 +14337bp (NM_201994.1), 1 168,386,625 3.03 0.34 VAMP4+18093bp (NM_003762.2) rs4342884 VAMP4 Intron4 (NM_201994.1), 1168,416,489 3.03 0.36 VAMP4 Intron4 (NM_003762.2) rs11691504 UBE2E3−377923bp (NM_182678.1), 2 181,292,695 3.11 0.82 UBE2E3 −378153bp(NM_006357.2) High-Risk Allele Frequency in Critical rate, Odds RatioOdds Ratio Nonprogressive Odds Ratio Genotype (Homozygote)(Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7)(Formula 8) rs11120527 0.21 1.77 2.79 2.49 2.05 rs10494994 0.16 1.932.76 3.29 1.97 rs6665581 0.27 1.69 2.72 3.73 1.38 rs12120152 0.27 1.692.72 3.73 1.38 rs2293325 0.67 1.74 2.69 2.74 1.41 rs6577539 0.87 2.402.69 ND ND rs34305923 0.62 1.69 2.66 2.43 1.23 rs1315219 0.45 1.67 2.632.78 1.54 rs10798603 0.24 1.77 2.60 3.30 1.65 rs1317252 0.82 2.10 2.514.36 2.10 rs12024194 0.13 1.95 2.44 4.16 1.86 rs10489250 0.13 1.91 2.283.12 1.91 rs271351 0.08 2.22 2.23 4.90 1.96 rs6689380 0.92 3.08 2.17 NDND rs9943293 0.23 1.71 2.16 2.67 1.65 rs4342884 0.25 1.72 2.11 2.81 1.52rs11691504 0.72 1.79 3.96 1.41 0.55

TABLE 31 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs9679229 UBE2E3 −350430bp (NM_182678.1), 2 181,320,188 3.05 0.82UBE2E3 −350660bp (NM_006357.2) rs11691031 C2orf29 −90020bp (NM_017546.3)2 101,237,876 1.36 0.49 rs714545 UBE2E3 −463121bp (NM_182678.1), 2181,207,497 3.54 0.81 UBE2E3 −463351bp (NM_006357.2) rs10931418 FLJ12519−41124bp (NM_032168.1) 2 190,090,541 0.90 0.65 rs4667078 UBE2E3−367916bp (NM_182678.1), 2 181,302,702 2.87 0.81 UBE2E3 −368146bp(NM_006357.2) rs1355216 SCN7A −183021bp (NM_002976.1) 2 167,352,006 3.140.86 rs11695159 FLJ12519 −22944bp (NM_032168.1) 2 190,108,721 0.79 0.64rs13032853 FLJ12519 Intron1 (NM_032168.1) 2 190,134,918 1.05 0.65rs733830 C2orf29 −91059bp (NM_017546.3) 2 101,236,837 1.54 0.49rs16833004 GLS −41329bp (NM_014905.2) 2 191,529,780 2.52 0.97 rs11563200TRPM8 Intron25 (NM_024080.3) 2 234,706,809 0.01 0.58 rs10930240 SCN7A−162624bp (NM_002976.1) 2 167,331,609 2.96 0.87 rs9287871 SCN7A−162839bp (NM_002976.1) 2 167,331,824 2.96 0.87 rs16860887 LOC91526Intron15 (NM_153697.1) 2 197,723,413 3.53 0.90 rs1840111 UBE2E3−484947bp (NM_182678.1), 2 181,185,671 3.05 0.77 UBE2E3 −485177bp(NM_006357.2) rs934706 NXPH2 −373561bp (XM_371573) 2 139,745,104 1.840.21 rs7420360 EPHA4 +369107bp (NM_004438.3) 2 221,739,147 0.50 0.41rs6739369 FLJ20701 Intron3 (NM_017933.3) 2 229,738,357 3.71 0.18rs4850410 LOC91526 Intron15 (NM_153697.1) 2 197,745,675 3.81 0.93rs1453054 UBE2E3 −485205bp (NM_182678.1), 2 181,185,413 3.18 0.78 UBE2E3−485435bp (NM_006357.2) High-Risk Allele Frequency in Critical rate,Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype (Homozygote)(Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP) (Formula 7)(Formula 8) rs9679229 0.72 1.77 3.90 1.41 0.55 rs11691031 0.42 1.34 3.851.62 2.75 rs714545 0.70 1.85 3.76 1.88 0.76 rs10931418 0.59 1.26 3.612.14 3.40 rs4667078 0.72 1.74 3.57 1.42 0.58 rs1355216 0.77 1.91 3.551.25 0.50 rs11695159 0.59 1.23 3.47 2.07 3.32 rs13032853 0.59 1.29 3.452.20 3.33 rs733830 0.41 1.38 3.31 1.73 2.57 rs16833004 0.92 2.77 3.291.02 0.15 rs11563200 0.57 1.01 3.27 0.70 0.35 rs10930240 0.78 1.86 3.251.26 0.53 rs9287871 0.78 1.86 3.25 1.26 0.53 rs16860887 0.81 2.15 3.232.07 0.82 rs1840111 0.66 1.71 3.22 1.84 0.79 rs934706 0.15 1.60 3.22 ND0.99 rs7420360 0.38 1.16 3.21 0.93 2.18 rs6739369 0.08 2.39 3.20 4.062.60 rs4850410 0.84 2.40 3.20 2.97 1.13 rs1453054 0.67 1.75 3.13 2.030.90

TABLE 32 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs10186570 UBE2E3 −482951bp (NM_182678.1), 2 181,187,667 2.67 0.78UBE2E3 −483181bp (NM_006357.2) rs4076919 FLJ10116 +86710bp (NM_018000.1)2 216,546,324 3.09 0.83 rs968871 FLJ32955 +20953bp (NM_153041.1) 2150,428,575 3.81 0.45 rs968873 FLJ32955 +20796bp (NM_153041.1) 2150,428,732 3.81 0.45 rs13426748 LOC91526 Intron15 (NM_153697.1) 2197,723,066 3.39 0.90 rs2564118 FLJ32312 Intron4 (NM_144709.1) 261,144,940 1.22 0.52 rs1468981 KLF7 +36314bp (NM_003709.1) 2 207,734,7210.36 0.59 rs1641385 FLJ32955 +20086bp (NM_153041.1) 2 150,429,442 3.710.45 rs16825626 FLJ20701 Intron3 (NM_017933.3) 2 229,744,146 3.38 0.17rs4261668 MYL1 Intron3 (NM_079422.1), 2 210,987,818 3.62 0.35 MYL1Intron3 (NM_079420.1) rs848241 FLJ32955 Intron3 (NM_153041.1) 2150,460,159 3.55 0.43 rs1196155 PPP1R1C Intron2 (XM_087137) 2182,746,778 3.43 0.68 rs1104870 ALK Intron15 (NM_004304.3) 2 29,366,0693.60 0.17 rs12692654 KCNH7 Intron2 (NM_033272.2), 2 163,309,182 3.360.77 KCNH7 Intron2 (NM_173162.1) rs4667333 FLJ32955 Intron3(NM_153041.1) 2 150,461,734 3.44 0.44 rs787433 LOC401014 +29562bp(XM_379141) 2 145,697,590 3.44 0.42 rs1196185 PPP1R1C Intron2(XM_087137) 2 182,710,465 3.33 0.67 rs10496018 LOC402072 +151618bp(XM_377741) 2 53,312,986 3.28 0.16 rs7582411 LOC91526 Intron15(NM_153697.1) 2 197,738,392 3.10 0.91 rs1529404 MYCN +99328bp(NM_005378.3) 2 16,137,052 3.29 0.88 rs1608976 FLJ32955 Intron3(NM_153041.1) 2 150,460,868 3.20 0.44 rs2701664 PPP1R1C Intron2(XM_087137) 2 182,734,170 3.22 0.67 rs1196160 PPP1R1C Intron3(XM_087137) 2 182,753,518 3.22 0.67 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype(Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP)(Formula 7) (Formula 8) rs10186570 0.68 1.65 3.08 1.62 0.71 rs40769190.73 1.80 3.07 1.92 0.86 rs968871 0.31 1.77 3.06 3.17 1.75 rs968873 0.311.77 3.06 3.17 1.75 rs13426748 0.81 2.11 3.06 2.01 0.82 rs2564118 0.451.32 3.06 1.97 0.70 rs1468981 0.56 1.12 3.04 0.99 0.46 rs1641385 0.321.75 2.97 3.13 1.73 rs16825626 0.08 2.27 2.94 3.11 2.51 rs4261668 0.231.81 2.91 3.39 1.81 rs848241 0.31 1.73 2.87 3.02 1.78 rs1196155 0.551.71 2.87 3.23 2.15 rs1104870 0.08 2.36 2.85 6.13 2.33 rs12692654 0.651.76 2.83 2.82 1.44 rs4667333 0.31 1.72 2.78 3.00 1.77 rs787433 0.301.72 2.78 3.29 1.54 rs1196185 0.55 1.68 2.78 3.08 2.11 rs10496018 0.072.29 2.72 2.53 2.53 rs7582411 0.83 2.13 2.71 2.16 0.89 rs1529404 0.791.98 2.67 6.63 3.70 rs1608976 0.31 1.70 2.67 3.00 1.81 rs2701664 0.551.66 2.61 2.94 2.00 rs1196160 0.55 1.66 2.61 2.94 2.00

TABLE 33 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs1358105 FLJ32955 +17818bp (NM_153041.1) 2 150,431,710 3.30 0.39 0.271.72 2.59 3.20 1.60 rs1724855 FLJ32955 Intron3 (NM_153041.1) 2150,455,469 3.22 0.43 0.31 1.68 2.56 2.86 1.72 rs17589066 DNAH7 Intron48(NM_018897.1) 2 196,522,530 3.05 0.83 0.72 1.82 2.53 4.89 2.95 rs31276FLJ20701 Intron3 (NM_017933.3) 2 229,746,025 3.08 0.19 0.11 2.02 2.536.18 2.03 rs7569506 FLJ39822 +44702bp (NM_173512.1) 2 165,535,617 3.150.85 0.76 1.87 2.53 3.48 1.81 rs16838454 KIAA1679 Intron9 (XM_046570) 2137,843,162 3.08 0.16 0.08 2.23 1.70 2.79 1.93 rs17041614 ITPR1 +16975bp(NM_002222.1) 3 4,881,056 1.28 0.75 0.69 1.37 3.98 0.79 0.33 rs784288MDS1 Intron2 (NM_004991.1) 3 170,453,933 3.72 0.79 0.67 1.85 3.79 7.544.94 rs6773050 CDGAP Intron10 (XM_291085) 3 120,606,504 2.34 0.64 0.531.53 3.56 2.99 3.29 rs6792308 ITPR1 +11521bp (NM_002222.1) 3 4,875,6021.14 0.73 0.67 1.33 3.52 0.83 0.37 rs1828652 PLSCR4 Intron6(NM_020353.1) 3 147,397,711 3.96 0.47 0.34 1.78 3.49 2.66 2.23 rs1877268LOC93556 +73662bp (XM_376284) 3 170,104,751 2.31 0.37 0.27 1.55 3.411.49 2.45 rs16852789 LOC93556 +75467bp (XM_376284) 3 170,106,556 2.310.37 0.27 1.55 3.41 1.49 2.45 rs11920980 LOC440985 −77863bp (XM_498948)3 154,176,162 1.13 0.57 0.50 1.30 3.36 1.54 0.59 rs7429749 FTHFD Intron1(NM_012190.2), 3 127,371,520 2.65 0.21 0.13 1.85 3.23 ND 2.16 FTHFDIntron1 (NM_144776.1) rs7624272 SEMA5B Intron1 (NM_018987.1) 3124,178,241 3.01 0.10 0.04 2.83 3.22 ND 3.06 rs6763643 MYRIP Intron3(NM_015460.1) 3 40,072,995 0.70 0.38 0.34 1.22 3.17 2.51 0.67 rs4685335RAFTLIN Intron4 (NM_015150.1) 3 16,423,640 0.62 0.47 0.43 1.19 3.15 1.222.39 rs12490570 LOC152118 −107632bp (XM_098163) 3 154,577,350 3.96 0.920.82 2.35 3.05 5.13 2.26 rs7371987 CCR3 +10346bp (NM_001837.2), 346,293,512 3.21 0.31 0.20 1.78 3.02 6.91 1.56 CCR3 +10346bp(NM_178329.1) rs3957816 PCCB −13296bp (NM_000532.2) 3 137,438,550 3.710.25 0.14 2.01 2.97 5.03 1.91 rs9839623 CCR3 +15697bp (NM_001837.2), 346,298,863 3.07 0.31 0.21 1.76 2.91 6.79 1.53 CCR3 +15697bp(NM_178329.1) rs17016781 RARB Intron3 (NM_000965.2), 3 25,580,890 3.620.65 0.51 1.72 2.88 2.77 1.46 RARB Intron3 (NM_016152.2)

TABLE 34 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs453570 CISH +6457bp (NM_013324.4), 3 50,612,473 3.25 0.67 0.55 1.682.88 3.30 1.85 CISH +6457bp (NM_145071.1) rs13096142 CCR3 −1944bp(NM_001837.2), 3 46,256,748 3.04 0.35 0.24 1.71 2.87 4.85 1.39 CCR3−1944bp (NM_178329.1) rs696518 STAG1 Intron21 (NM_005862.1) 3137,602,998 3.63 0.28 0.16 1.94 2.87 4.86 1.74 rs6446245 DOCK3 Intron5(NM_004947.2) 3 51,012,298 3.15 0.66 0.54 1.65 2.80 3.11 2.26 rs16833788SEMA5B −6558bp (NM_018987.1) 3 124,236,700 3.37 0.10 0.03 3.22 2.78 ND3.29 rs6440881 LOC152118 −56902bp (XM_098163) 3 154,628,080 3.51 0.900.80 2.10 2.74 6.57 3.53 rs10510568 RARB Intron3 (NM_000965.2), 325,577,736 3.24 0.64 0.52 1.67 2.70 2.90 1.58 RARB Intron3 (NM_016152.2)rs16833786 SEMA5B −5978bp (NM_018987.1) 3 124,236,120 3.26 0.10 0.033.16 2.68 ND 3.23 rs1545105 LOC389100 +81379bp (XM_374035) 3 29,199,6913.01 0.37 0.26 1.68 2.67 2.20 2.04 rs9883170 LOC389100 +82213bp(XM_374035) 3 29,198,857 3.04 0.37 0.26 1.69 2.64 2.26 2.00 rs17016778RARB Intron3 (NM_000965.2), 3 25,580,286 3.28 0.64 0.52 1.67 2.61 2.731.53 RARB Intron3 (NM_016152.2) rs2174746 LOC152118 −103841bp(XM_098163) 3 154,581,141 3.52 0.92 0.83 2.26 2.61 5.02 2.39 rs11712746KCNMB2 −262329bp (NM_181361.1), 3 179,474,597 3.12 0.25 0.15 1.87 2.606.36 1.74 KCNMB2 −284723bp (NM_005832.3) rs684773 PCCB −12843bp(NM_000532.2) 3 137,439,003 3.26 0.22 0.13 1.98 2.58 5.71 1.84 rs695983STAG1 Intron29 (NM_005862.1) 3 137,547,245 3.33 0.24 0.14 1.94 2.58 5.201.72 rs1154988 LOC391581 −434bp (XM_497940) 3 137,407,889 3.23 0.23 0.131.98 2.55 5.68 1.85 rs2232248 HEMK1 Exon3 (NM_016173.1) 3 50,584,6283.11 0.66 0.55 1.65 2.55 2.94 1.85 rs696081 PCCB Intron13 (NM_000532.2)3 137,529,887 3.21 0.26 0.16 1.86 2.49 4.24 1.72 rs2140450 PPP2R3AIntron5 (NM_002718.3), 3 137,252,444 3.01 0.33 0.23 1.72 2.47 3.87 1.50PPP2R3A Intron4 (NM_181897.1)

TABLE 35 High-Risk High-Risk Allele Allele Frequency Odds Odds Frequencyin Non- Critical Ratio Ratio Critical in Pro- prog- Odds rate, (Homo-(Hetero- Chro- rate, gressive ressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs6440874 LOC152118 −101011bp (XM_098163) 3 154,583,971 3.33 0.92 0.832.21 2.45 4.99 2.44 rs9852831 LOC152118 −133737bp (XM_098163) 3154,551,245 3.19 0.90 0.82 2.08 2.43 5.05 2.57 rs9822326 LOC339894Intron2 (XM_379230) 3 158,286,267 3.17 0.54 0.42 1.64 2.41 2.56 1.39rs548288 PCCB Intron1 (NM_000532.2) 3 137,452,453 3.09 0.23 0.13 1.912.34 4.47 1.76 rs7428299 EDEM1 +469242bp (XM_376201) 3 5,705,884 3.020.68 0.56 1.64 2.27 2.67 1.81 rs12648912 PAPSS1 +17033bp (NM_005443.4) 4108,875,394 3.91 0.64 0.51 1.76 3.67 2.92 1.24 rs1865328 LYAR +1510bp(NM_017816.1) 4 4,386,001 0.23 0.50 0.48 1.08 3.41 1.21 0.48 rs531823QDPR +272295bp (NM_000320.1) 4 16,891,997 3.28 0.64 0.51 1.67 2.94 1.780.67 rs2642849 UGT2B4 +7559bp (NM_021139.1) 4 70,519,085 3.18 0.55 0.431.64 2.90 2.77 2.13 rs2736463 UGT2B4 +17920bp (NM_021139.1) 4 70,508,7243.08 0.55 0.43 1.63 2.86 2.72 2.15 rs11734419 MAML3 Intron2(NM_018717.2) 4 141,040,368 3.22 0.46 0.34 1.67 2.79 2.64 1.96rs12502059 PAPSS1 Intron4 (NM_005443.4) 4 108,962,816 3.03 0.61 0.491.64 2.75 2.62 1.22 rs4697446 DHX15 +259479bp (NM_001358.1) 4 23,945,8913.30 0.38 0.26 1.73 2.67 3.40 1.64 rs7692155 KIAA1109 −44906bp(XM_371706) 4 123,386,649 3.06 0.72 0.61 1.67 2.60 3.39 2.28 rs17605639LOC389204 −297625bp (XM_374079) 4 27,290,099 3.09 0.80 0.70 1.76 2.503.93 2.53 rs584374 PPARGC1A −165848bp (NM_013261.2) 4 23,733,817 3.550.11 0.04 3.20 1.90 5.93 1.94 rs17134333 EPB41L4A Intron2 (NM_022140.2)5 111,670,626 2.67 0.71 0.60 1.63 3.71 1.80 0.69 rs7718321 EPB41L4AIntron1 (NM_022140.2) 5 111,697,251 0.93 0.69 0.64 1.27 3.38 0.94 0.42rs7712363 LOC389319 −181104bp (XM_374134) 5 125,542,548 1.03 0.76 0.711.32 3.38 0.59 0.28 rs10076364 LOC389319 −212764bp (XM_374134) 5125,510,888 0.93 0.75 0.70 1.29 3.27 0.67 0.32 rs7703461 SV2C Intron3(XM_043493) 5 75,529,168 3.78 0.40 0.27 1.80 3.27 3.99 1.35 rs194229MGC10067 −22589bp (NM_145049.1) 5 158,600,287 1.24 0.50 0.43 1.32 3.201.57 2.53 rs10478702 LOC389319 −173069bp (XM_374134) 5 125,550,583 1.040.76 0.70 1.32 3.19 0.71 0.33 rs17134365 EPB41L4A Intron1 (NM_022140.2)5 111,694,455 1.04 0.72 0.66 1.30 3.12 0.92 0.42 rs11743891 FSTL4Intron3 (XM_048786) 5 132,838,807 0.29 0.42 0.40 1.10 3.11 1.75 0.58rs166296 SEMA6A Intron3 (NM_020796.2) 5 115,861,466 3.48 0.38 0.26 1.763.07 4.18 1.40 rs17731499 KIBRA Intron1 (NM_015238.1) 5 167,697,178 3.530.25 0.14 1.97 3.04 9.22 1.51

TABLE 36 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs2055375 LOC441075 +72079bp (XM_499000) 5 60,566,977 3.56 0.26 0.151.97 3.03 7.10 1.84 rs1560026 LOC389319 −225968bp (XM_374134) 5125,497,684 0.82 0.74 0.69 1.26 3.00 0.67 0.33 rs16869864 PTGER4−300343bp (NM_000958.2) 5 40,415,446 3.36 0.21 0.12 2.04 2.96 5.54 2.19rs7736074 SLC6A19 −12310bp (XM_291120) 5 1,242,456 3.35 0.65 0.52 1.692.76 3.00 2.07 rs581318 LOC441075 +56653bp (XM_499000) 5 60,551,551 3.240.25 0.15 1.89 2.75 6.89 1.73 rs30182 SV2C −30159bp (XM_043493) 575,384,836 3.46 0.84 0.73 1.89 2.74 4.40 2.54 rs7723981 PTGER4 −275120bp(NM_000958.2) 5 40,440,669 3.16 0.20 0.11 2.04 2.67 5.19 2.13 rs10473185PTGER4 −304865bp (NM_000958.2) 5 40,410,924 3.06 0.20 0.11 2.00 2.585.23 2.09 rs10041973 ZSWIM6 −51723bp (XM_035299) 5 60,612,035 3.19 0.110.04 2.75 2.48 ND 2.55 rs4958734 GALNT10 Intron9 (NM_198321.2), 5153,769,698 3.05 0.94 0.87 2.33 2.36 4.20 1.77 GALNT10 Intron2(NM_017540.3) rs10079115 ZSWIM6 −71664bp (XM_035299) 5 60,592,094 3.040.11 0.04 2.68 2.34 ND 2.48 rs4379148 ZSWIM6 −72613bp (XM_035299) 560,591,145 3.03 0.11 0.04 2.75 2.32 ND 2.53 rs1501905 SV2C Intron1(XM_043493) 5 75,433,640 3.04 0.79 0.68 1.73 2.29 3.12 1.94 rs30196 SV2C−1688bp (XM_043493) 5 75,413,307 3.06 0.78 0.67 1.72 2.25 2.77 1.65rs158563 LOC91942 Intron1 (NM_174889.2) 5 60,290,761 3.44 0.20 0.10 2.192.19 4.28 1.69 rs10939888 ZSWIM6 −72737bp (XM_035299) 5 60,591,021 3.000.14 0.07 2.26 2.16 6.78 2.02 rs12696980 ZSWIM6 −71733bp (XM_035299) 560,592,025 3.00 0.14 0.07 2.26 2.16 6.78 2.02 rs2328883 LRRC16 −108438bp(NM_017640.2) 6 25,510,510 1.85 0.33 0.25 1.49 3.89 11.95 0.95 rs531970EPHA7 −35391bp (NM_004440.2) 6 94,221,384 1.06 0.46 0.40 1.28 3.84 2.250.65 rs880226 LRRC16 −108666bp (NM_017640.2) 6 25,510,282 2.02 0.33 0.241.53 3.80 11.95 0.99 rs9469615 MLN −45140bp (NM_002418.1) 6 33,924,9111.24 0.86 0.81 1.45 3.52 0.18 0.08 rs600709 NCOA7 Intron2 (NM_181782.2)6 126,175,082 2.48 0.88 0.80 1.80 3.48 0.39 0.16 rs7767107 LOC441173Intron1 (XM_496827) 6 142,237,572 3.49 0.30 0.19 1.86 3.35 2.24 2.29rs1336272 LOC441173 −23126bp (XM_496827) 6 142,286,367 3.54 0.31 0.191.86 3.31 2.37 2.25 rs595805 NRN1 −34495bp (NM_016588.2) 6 5,987,1271.27 0.65 0.58 1.33 3.31 1.29 0.54 rs763075 LOC442255 +235684bp(XM_498140) 6 122,253,219 0.20 0.71 0.69 1.08 3.23 0.41 0.22

TABLE 37 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs13213414 LOC441173 Intron1 (XM_496827) 6 142,262,919 3.60 0.31 0.191.87 3.15 2.59 2.17 rs16886390 TMEM30A Intron1 (NM_018247.1) 676,038,298 1.18 0.87 0.82 1.47 3.14 0.78 0.27 rs1322867 TBX18 −222373bp(XM_496819) 6 85,752,991 1.35 0.35 0.28 1.38 3.14 1.00 2.24 rs2152589LOC441173 Intron1 (XM_496827) 6 142,250,761 3.51 0.31 0.20 1.85 3.142.52 2.17 rs3798425 MYO6 Intron29 (XM_376516) 6 76,664,270 2.57 0.830.74 1.70 3.13 1.29 0.56 rs9496008 LOC441173 +181779bp (XM_496827) 6141,762,720 3.74 0.54 0.40 1.73 3.04 3.06 1.62 rs9349248 PHACTR1−204207bp (XM_166420) 6 12,621,612 0.77 0.57 0.52 1.22 3.03 1.32 0.55rs12200432 PHACTR1 −201248bp(XM_166420) 6 12,624,571 0.44 0.58 0.55 1.143.01 1.09 0.49 rs6570564 LOC285740 +20195bp (XM_379438) 6 143,896,9653.35 0.52 0.40 1.67 3.00 2.89 2.05 rs9399445 LOC285740 +16163bp(XM_379438) 6 143,900,997 3.41 0.55 0.42 1.68 2.97 2.98 2.01 rs4713376C6orf214 +7329bp (NM_207496.1) 6 30,881,293 3.37 0.17 0.08 2.27 2.943.11 2.51 rs9484507 LOC441173 +179848bp (XM_496827) 6 141,764,651 3.930.53 0.39 1.80 2.93 2.98 1.58 rs9379712 C6orf32 −187336bp (NM_015864.2)6 25,172,898 3.15 0.59 0.47 1.64 2.92 2.80 1.28 rs7754052 LOC441173Intron1 (XM_496827) 6 142,254,496 3.20 0.32 0.21 1.77 2.88 2.37 2.09rs9496179 LOC441173 Intron1 (XM_496827) 6 142,254,945 3.20 0.32 0.211.77 2.88 2.37 2.09 rs2039560 LOC441173 +145925bp (XM_496827) 6141,798,574 3.40 0.67 0.54 1.70 2.84 3.04 1.71 rs10485223 PRDM13+130551bp (NM_021620.2) 6 100,300,726 3.31 0.79 0.68 1.80 2.83 4.45 2.68rs4240580 PRDM13 +138012bp (NM_021620.2) 6 100,308,187 3.51 0.79 0.681.82 2.81 3.79 2.25 rs9393611 C6orf32 −188810bp (NM_015864.2) 625,174,372 3.03 0.59 0.47 1.62 2.79 2.70 1.26 rs9356960 C6orf32−188588bp (NM_015864.2) 6 25,174,150 3.07 0.59 0.47 1.63 2.78 2.81 1.33rs9367520 ELOVL5 Intron1 (NM_021814.2) 6 53,271,883 3.41 0.35 0.23 1.822.76 4.12 1.62 rs12195469 C6orf214 Intron1 (NM_207496.1) 6 30,897,5873.21 0.16 0.08 2.22 2.75 3.06 2.43 rs17826560 PRDM13 +132124bp(NM_021620.2) 6 100,302,299 3.29 0.79 0.68 1.79 2.73 4.08 2.50 rs1915463VMP −52946bp (NM_080723.2) 6 24,181,383 3.24 0.53 0.41 1.66 2.61 2.721.84 rs17070891 LOC441173 +153727bp (XM_496827) 6 141,790,772 3.27 0.550.42 1.66 2.60 2.79 1.61 rs1402406 VMP −35757bp (NM_080723.2) 624,198,572 3.06 0.57 0.45 1.62 2.59 2.63 2.00 rs10947096 C6orf214+14748bp (NM_207496.1) 6 30,873,874 3.08 0.13 0.06 2.44 2.57 ND 2.47

TABLE 38 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs9403498 FUCA2 −18431bp (NM_032020.3) 6 143,892,987 3.04 0.63 0.51 1.632.56 2.89 2.01 rs1402405 VMP −35853bp (NM_080723.2) 6 24,198,476 3.130.58 0.45 1.63 2.53 2.63 1.91 rs7740547 SLC22A16 Intron1 (NM_033125.2) 6110,897,601 3.13 0.49 0.37 1.64 2.43 2.66 1.33 rs221712 SLC22A16 Intron4(NM_033125.2) 6 110,869,519 3.18 0.49 0.37 1.65 2.39 2.64 1.39rs17577123 C6orf10 +2945bp (NM_006781.2) 6 32,365,525 3.07 0.11 0.042.71 1.95 3.88 2.47 rs7802749 PPP1R9A Intron4 (XM_371933) 7 94,432,2921.20 0.53 0.46 1.32 3.58 1.78 0.61 rs6965857 DLD −36997bp (NM_000108.2)7 107,088,565 0.76 0.65 0.60 1.23 3.13 1.00 0.45 rs11972734 CREB3L2−6085bp (NM_194071.1) 7 137,150,143 3.19 0.26 0.16 1.86 3.12 15.95 1.54rs1621819 C1GALT1 +30350bp (NM_020156.1) 7 7,087,571 3.80 0.61 0.47 1.763.11 3.14 2.03 rs1514880 LOC340268 Intron1 (XM_294634) 7 9,664,527 3.390.60 0.46 1.70 3.09 3.25 2.24 rs12669138 LOC340268 Intron1 (XM_294634) 79,564,997 2.83 0.65 0.54 1.60 3.08 3.15 2.74 rs698408 SND1 Intron8(NM_014390.1) 7 126,939,887 2.61 0.30 0.21 1.66 3.03 1.55 2.28 rs7458284LOC340268 Intron1 (XM_294634) 7 9,670,774 3.37 0.39 0.27 1.74 2.87 3.811.44 rs3757760 SND1 Intron16 (NM_014390.1) 7 127,252,147 3.23 0.30 0.191.81 2.85 2.51 2.08 rs2241291 SND1 Intron16 (NM_014390.1), 7 127,232,8253.27 0.30 0.19 1.81 2.81 2.63 2.04 NAG8 Exon1 (NM_014411.1) rs17156635CREB5 Intron1 (NM_182899.2), 7 28,168,969 3.16 0.23 0.13 1.99 2.80 14.751.50 CREB5 −56415bp (NM_182898.1), CREB5 −79505bp (NM_004904.1)rs1638213 C1GALT1 +33234bp (NM_020156.1) 7 7,090,455 3.36 0.60 0.47 1.672.72 2.82 1.90 rs320785 LOC340268 −6464bp (XM_294634) 7 9,532,629 3.410.59 0.46 1.68 2.71 2.84 1.73 rs1796121 C1GALT1 +33624bp (NM_020156.1) 77,090,845 3.24 0.59 0.47 1.65 2.58 2.74 1.84 rs3757759 SND1 Intron16(NM_014390.1) 7 127,288,765 3.12 0.33 0.22 1.74 2.57 3.27 1.80rs12530870 KIAA1706 −11363bp(NM_030636.1) 7 35,954,741 3.00 0.81 0.711.76 2.42 3.98 2.76 rs17152703 LOC401384 +195612bp (XM_379506) 778,929,412 3.33 0.85 0.75 1.89 2.37 3.41 2.01 rs10441198 LOC442363−76453bp (XM_498255) 7 144,098,654 3.17 0.60 0.48 1.64 2.36 2.41 1.33

TABLE 39 High-Risk High-Risk Allele Allele Frequency Odds Odds Frequencyin Non- Critical Ratio Ratio Critical in Pro- prog- Odds rate, (Homo-(Hetero- Chro- rate, gressive ressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs13225076 LOC285984 −162101bp (XM_208373) 7 84,095,361 3.16 0.86 0.761.93 2.31 3.53 1.92 rs17171658 C7orf11 +13816bp (NM_138701.1) 739,931,767 3.02 0.78 0.67 1.75 2.31 2.98 1.70 rs826824 CNTNAP2 Intron9(NM_014141.3) 7 146,496,639 3.04 0.74 0.63 1.69 2.26 2.60 1.52 rs6993934FBXO16 +12541bp (NM_172366.2) 8 28,329,307 0.01 0.27 0.27 1.00 3.56 0.371.81 rs1425735 EBF2 +148803bp (NM_022659.1) 8 25,608,687 1.50 0.66 0.581.38 3.28 1.37 0.57 rs6991277 PTDSS1 +53377bp (NM_014754.1) 8 97,469,3273.10 0.93 0.85 2.28 3.26 0.74 0.26 rs6981589 LOC286186 Intron1(XM_379586) 8 66,612,011 2.30 0.66 0.56 1.52 3.13 2.85 3.04 rs4394361LOC157657 −172125bp (NM_177965.2) 8 96,522,738 3.55 0.24 0.13 2.04 3.0910.03 1.97 rs3133744 LOC157657 −252889bp (NM_177965.2) 8 96,603,502 3.530.31 0.19 1.90 2.97 4.79 1.84 rs10113800 LOC157657 −163565bp(NM_177965.2) 8 96,514,178 3.12 0.23 0.14 1.92 2.70 10.58 1.76 rs6601569C8orf7 −14730bp (XM_088376) 8 11,110,988 3.45 0.93 0.85 2.32 2.66 7.143.26 rs10105301 LOC286186 +84181bp (XM_379586) 8 66,517,616 3.04 0.270.17 1.81 2.63 2.22 2.10 rs6995270 SIAT4A Intron2 (NM_003033.2), 8134,582,401 3.02 0.51 0.39 1.62 2.37 2.71 1.49 SIAT4A Intron2(NM_173344.1) rs10811638 CDKN42A +44473bp (NM_000077.3), 9 21,913,2790.15 0.42 0.41 1.06 3.80 0.84 2.27 CDKN2A +44473bp (NM_058197.2), CDKN2A+44473bp (NM_058195.2) rs10869589 PCSK5 −314572bp (NM_006200.2) 975,420,603 2.09 0.72 0.63 1.52 3.59 5.09 5.18 rs10967964 MOBKL2B Intron1(NM_024761.3) 9 27,485,920 3.13 0.23 0.13 1.95 3.55 1.34 2.62 rs2518713CDKN2A +38086bp (NM_000077.3), 9 21,919,666 0.38 0.44 0.41 1.13 3.391.01 2.32 CDKN2A +38086bp (NM_058197.2), CDKN2A +38086bp (NM_058195.2)rs10781440 LOC392347 Intron1 (XM_373298) 9 68,992,320 3.89 0.37 0.241.85 3.34 3.48 1.97 rs1412066 DBC1 −33786bp (NM_014618.1) 9 119,245,0413.06 0.93 0.85 2.19 3.25 0.97 0.35 rs7022939 LOC347273 +139903bp(XM_294592) 9 100,568,349 1.91 0.36 0.28 1.48 3.21 1.32 2.30 rs4744780PCSK5 Intron9 (NM_006200.2) 9 75,952,602 3.30 0.50 0.37 1.68 3.18 2.852.21

TABLE 40 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs4743420 LOC347273 +139198bp (XM_294592) 9 100,567,644 1.93 0.36 0.271.49 3.17 1.33 2.29 rs10815959 PTPRD −82533bp (NM_002839.1), 9 8,806,4793.11 0.58 0.46 1.63 3.15 2.73 2.41 PTPRD −82533bp (NM_130391.1), PTPRD−82533bp (NM_130392.1), PTPRD −82533bp (NM_130393.1) rs953924 FLJ31810Intron3 (NM_152570.1) 9 28,313,673 2.54 0.85 0.77 1.74 3.10 18.06 14.20rs4836767 DBC1 −34887bp (NM_014618.1) 9 119,246,142 3.24 0.93 0.85 2.243.09 1.46 0.53 rs4977749 CDKN2A +40425bp (NM_000077.3), 9 21,917,3270.38 0.44 0.41 1.13 3.09 1.02 2.22 CDKN2A +40425bp (NM_058197.2), CDKN2A+40425bp (NM_058195.2) rs10512277 LOC347273 +138909bp (XM_294592) 9100,567,355 2.02 0.36 0.27 1.50 3.08 1.41 2.27 rs9299341 LOC347273+141993bp (XM_294592) 9 100,570,439 2.02 0.36 0.27 1.50 3.08 1.41 2.27rs10491692 DOCK8 Intron13 (NM_203447.1) 9 336,887 0.35 0.16 0.14 1.173.08 0.00 1.80 rs2780197 C9orf39 Intron13 (NM_017738.1) 9 17,416,1863.83 0.81 0.70 1.90 3.05 3.93 2.16 rs7038186 C9orf39 Intron10(NM_017738.1) 9 17,388,616 3.69 0.81 0.69 1.87 2.96 3.91 2.20 rs2773395C9orf28 −119663bp (XM_088525) 9 126,049,019 3.39 0.36 024 1.77 2.94 2.981.97 rs1412067 DBC1 −35540bp (NM_014618.1) 9 119,246,795 3.08 0.93 0.852.20 2.92 1.45 0.54 rs11144406 OSTF1 +226491bp (NM_012383.3) 975,217,808 3.39 0.20 0.11 2.10 2.91 5.39 2.22 rs10869690 PIP5K1BIntron15 (NM_003558.1) 9 68,851,241 3.37 0.38 0.26 1.74 2.85 3.90 1.51rs10969339 LOC401497 +655774bp (XM_376822) 9 29,723,159 3.13 0.88 0.791.95 2.77 11.71 6.74 rs16929359 DMRT2 +392458bp (NM_006557.3), 91,440,010 3.62 0.11 0.04 3.02 2.70 ND 2.53 DMRT2 +392458bp (NM 181872.1)rs943509 OSTF1 +226788bp (NM_012383.3) 9 75,218,105 3.18 0.37 0.25 1.722.70 3.80 1.45 rs10869686 PIP5K1B Intron15 (NM_003558.1) 9 68,850,1683.22 0.37 0.26 1.73 2.68 3.74 1.52 rs10869553 OSTF1 +235138bp(NM_012383.3) 9 75,226,455 3.09 0.20 0.11 2.01 2.62 5.19 2.10 rs12554461RCL1 +4195bp (NM_005772.2) 9 4,855,256 3.19 0.41 0.29 1.69 2.60 2.491.90 rs4142436 DMRT2 +396648bp (NM_006557.3), 9 1,444,200 3.23 0.13 0.062.49 2.54 3.92 2.56 DMRT2 +396648bp (NM 181872.1)

TABLE 41 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs7048937 LOC392347 Intron2 (XM_373298) 9 68,975,807 3.16 0.38 0.27 1.702.52 2.57 1.85 rs7034303 LOC392347 Intron2 (XM_373298) 9 68,976,425 3.160.38 0.27 1.70 2.52 2.57 1.85 rs6560584 LOC392347 Intron2 (XM_373298) 968,976,726 3.16 0.38 0.27 1.70 2.52 2.57 1.85 rs7850573 LOC392347Intron2 (XM_373298) 9 68,976,814 3.16 0.38 0.27 1.70 2.52 2.57 1.85rs2584554 C9orf39 Intron13 (NM_017738.1) 9 17,416,808 3.13 0.80 0.701.78 2.50 3.38 1.91 rs1547335 LOC401497 +621065bp (XM_376822) 929,757,868 3.11 0.77 0.66 1.73 2.25 2.90 1.82 rs3781158 KCNMA1 Intron18(NM_002247.2) 10 78,426,444 1.61 0.60 0.51 1.39 3.96 1.65 0.59rs10823349 HK1 Intron5 (NM_033497.1), 10 70,779,704 3.56 0.90 0.80 2.133.90 1.05 0.39 HK1 Intron5 (NM_033498.1), HK1 Intron6 (NM_033500.1), HK1Intron2 (NM_033496.1), HK1 Intron2 (NM 000188.1) rs17388160 KCNMA1Intron18 (NM_002247.2) 10 78,415,943 1.81 0.66 0.57 1.44 3.79 1.47 0.57rs1801041 DNA2L Exon21 (XM_166103) 10 69,844,713 1.49 0.80 0.73 1.453.58 0.78 0.33 rs11001963 KCNMA1 Intron18 (NM_002247.2) 10 78,430,9652.23 0.70 0.60 1.52 3.57 1.55 0.63 rs4454609 PHYH +15499bp (NM_006214.2)10 13,344,307 2.46 0.66 0.55 1.55 3.56 3.42 3.45 rs4589168 HK1 Intron10(NM_033497.1), 10 70,800,223 3.18 0.89 0.81 2.01 3.45 1.15 0.45 HK1Intron10 (NM_033498.1), HK1 Intron11 (NM_033500.1), HK1 Intron7(NM_033496.1), HK1 Intron7 (NM_000188.1) rs7093891 XPNPEP1 +21493bp(NM_020383.2) 10 111,593,021 3.00 0.69 0.57 1.64 3.31 2.15 0.92rs10762840 LOC283050 Intron4 (XM_378238) 10 80,483,339 3.86 0.39 0.261.81 3.12 3.29 1.83 rs9416465 ZWINT +273128bp (NM_007057.2), 1057,514,084 3.32 0.82 0.71 1.85 2.78 3.55 1.81 ZWINT +273128bp(NM_032997.1) rs7903897 LOC285444 +40505bp (XM_497256) 10 135,321,5663.05 0.61 0.49 1.63 2.72 2.68 2.21

TABLE 42 High-Risk High-Risk Allele Allele Frequency Odds Odds Frequencyin Non- Critical Ratio Ratio Critical in Pro- prog- Odds rate, (Homo-(Hetero- Chro- rate, gressive ressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs2496057 C10orf112 Intron20 (XM_295865) 10 19,623,674 3.05 0.56 0.441.62 2.57 2.75 1.90 rs1500763 ZWINT +308458bp (NM_007057.2), 1057,478,754 3.03 0.86 0.77 1.88 2.54 5.27 2.80 ZWINT +308458bp(NM_032997.1) rs2151078 PCDH15 Intron3 (NM_033056.2) 10 55,864,965 3.110.95 0.88 2.49 2.21 3.40 1.37 rs1881716 LDHA Intron5 (NM_005566.1) 1118,381,594 3.40 0.38 0.26 1.74 3.86 2.09 2.48 rs7107489 LOC119710+809442bp (NM_138787.2) 11 37,446,835 1.46 0.65 0.58 1.37 3.69 2.69 3.66rs6590698 SPAS1 +396277bp (NM_174927.1) 11 132,819,450 1.09 0.72 0.661.32 3.60 5.44 6.70 rs4274186 LDHA Intron2 (NM_005566.1) 11 18,375,2953.41 0.38 0.26 1.76 3.58 2.15 2.41 rs7927545 MGC71806 Intron3(NM_198516.1) 11 11,403,040 3.75 0.60 0.46 1.73 3.58 3.11 1.30rs10792820 PICALM Intron12 (NM_007166.1) 11 85,381,622 0.44 0.49 0.461.15 3.46 1.48 0.53 rs9326253 LOC440070 +34118bp (XM_498530) 11119,149,661 0.13 0.60 0.59 1.05 3.27 0.73 0.36 rs12576681 MGC71806Intron3 (NM_198516.1) 11 11,402,663 3.67 0.31 0.19 1.88 3.23 6.26 1.53rs10837846 LOC387761 −159308bp (XM_373495) 11 42,393,594 2.69 0.59 0.471.57 3.09 3.22 2.55 rs1462674 LOC387761 −160223bp (XM_373495) 1142,394,509 2.71 0.59 0.47 1.57 3.07 3.22 2.53 rs1386239 LOC338645Intron5 (XM_370616) 11 24,774,285 2.73 0.11 0.05 2.48 3.06 0.00 3.10rs10837854 LOC387761 −227349bp (XM_373495) 11 42,461,635 2.09 0.56 0.471.47 3.05 2.58 2.69 rs504105 FLJ37874 +3946bp (NM_182603.1) 1182,641,607 3.17 0.57 0.45 1.64 3.05 2.97 1.30 rs524441 FLJ37874 +1045bp(NM_182603.1) 11 82,638,706 3.11 0.56 0.44 1.63 2.93 2.90 1.29 rs681367FLJ37874 +1111bp (NM_182603.1) 11 82,638,772 3.10 0.56 0.44 1.63 2.912.90 1.31 rs628223 MDS025 +4340bp (NM_021825.3) 11 82,645,812 3.10 0.560.44 1.63 2.91 2.90 1.31 rs6484897 MGC71806 Intron3 (NM_198516.1) 1111,401,879 3.15 0.31 0.20 1.78 2.90 5.97 1.41 rs4937173 KIRREL3 Intron1(NM 032531.1) 11 126,034,466 3.37 0.43 0.31 1.71 2.90 2.75 1.96rs11220587 KIRREL3 Intron1 (NM_032531.1) 11 126,082,725 3.35 0.50 0.371.68 2.88 2.99 1.31 rs2252070 MMP13 −77bp (NM_002427.2) 11 102,331,7493.46 0.60 0.47 1.69 2.82 2.88 1.55 rs693253 KIRREL3 Intron1(NM_032531.1) 11 126,032,975 3.40 0.44 0.31 1.71 2.77 2.85 1.82rs4937174 KIRREL3 Intron1 (NM_032531.1) 11 126,034,593 3.21 0.43 0.311.68 2.74 2.66 1.92

TABLE 43 High- Risk Allele High-Risk Fre- Allele quency Frequency OddsOdds in Pro- in Non- Critical Ratio Ratio Critical gressive pro- Oddsrate, (Homo- (Hetero- Chro- rate, Glau- gressive Ratio Geno- zygote)zygote) mo- Physical Allele coma Glaucoma (For- type (For- (For-DBSNP_ID Exon, Intron some Location (−logP) Group Group mula 6) (−logP)mula 7) mula 8) rs12800710 LPXN Intron7 (NM_004811.1) 11 58,071,116 3.730.87 0.77 2.04 2.73 3.91 2.08 rs10898459 EED Intron6 (NM_003797.2), 1185,650,587 3.14 0.60 0.48 1.64 2.72 2.89 2.06 EED Intron6 (NM_152991.1)rs3862632 KIRREL3 Intron1 (NM_032531.1) 11 126,054,713 3.21 0.43 0.311.68 2.66 2.70 1.86 rs11229555 CNTF +15485bp (NM_000614.2), 1158,165,263 3.57 0.87 0.77 2.01 2.59 3.88 2.12 ZFP91-CNTF +15485bp(NM_170768.1) rs1451316 OR1S2 +1990bp (XM 166916) 11 57,725,262 3.060.53 0.41 1.63 2.58 2.53 1.97 rs7108068 KIRREL3 Intron1 (NM_032531.1) 11126,035,753 3.18 0.43 0.31 1.67 2.58 2.74 1.79 rs10896715 OR1S1 +5325bp(XM_166917) 11 57,745,095 3.38 0.84 0.74 1.88 2.51 3.08 1.65 rs2298608CNTF +11265bp (NM_000614.2), 11 58,161,043 3.47 0.87 0.77 1.99 2.51 3.832.12 ZFP91-CNTF +11265bp (NM_170768.1) rs655316 MMP13 −5902bp(NM_002427.2) 11 102,337,574 3.07 0.58 0.46 1.62 2.49 2.74 1.57 rs161130LOC387810 −172677bp (XM_373513) 11 112,160,184 3.15 0.83 0.73 1.83 2.353.18 1.78 rs7102784 LOC399898 +878bp (XM_374885) 11 57,813,314 3.08 0.880.79 1.94 2.25 3.65 1.98 rs11175627 LOC400046 +33814bp (XM_378362) 1263,691,379 3.08 0.27 0.17 1.83 3.15 16.90 1.47 rs7302136 DKFZp761O2018+35186bp (XM_044062) 12 127,752,520 3.91 0.94 0.85 2.54 3.13 5.80 2.27rs11175622 LOC400046 +28983bp (XM 378362) 12 63,686,548 2.98 0.27 0.171.79 3.10 16.58 1.46 rs7136577 LOC400046 +35244bp (XM_378362) 1263,692,809 2.98 0.27 0.17 1.79 3.10 16.58 1.46 rs2169856 LOC441639+48092bp (XM_497345) 12 53,858,919 1.26 0.72 0.66 1.35 3.06 0.97 0.45rs7962260 FLJ40126 Intron18 (NM_173599.1), 12 38,510,570 3.77 0.24 0.132.07 3.05 8.32 1.68 SLC2A13 Intron6 (NM_052885.1) rs7296095 LOC440112−115952bp (XM_498548) 12 114,337,597 2.55 0.28 0.19 1.68 3.05 10.32 1.19rs7959848 LOC401725 +200037bp (XM_377278) 12 82,248,474 3.88 0.45 0.321.79 3.02 3.10 1.75 rs12227382 DKFZp761O2018 +36420bp (XM_044062) 12127,753,754 3.72 0.94 0.85 2.48 2.94 5.75 2.33 rs11059865 DKFZp761O2018+34801bp (XM_044062) 12 127,752,135 3.58 0.94 0.86 2.48 2.92 4.34 1.67rs4882448 LOC401725 +200630bp (XM_377278) 12 82,249,067 3.62 0.44 0.311.76 2.85 3.01 1.76 rs4473002 FLJ40126 Intron18 (NM_173599.1), 1238,541,898 3.40 0.24 0.14 1.97 2.82 8.19 1.58 SLC2A13 Intron6(NM_052885.1)

TABLE 44 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs7968509 FLJ40126 Intron18 (NM_173599.1), 12 38,541,115 3.46 0.24 0.131.99 2.82 7.74 1.66 SLC2A13 Intron6 (NM_052885.1) rs7956512 LOC401725+199585bp (XM_377278) 12 82,248,022 3.71 0.46 0.32 1.75 2.79 2.82 1.72rs4768188 FLJ40126 Intron18 (NM_173599.1), 12 38,507,445 3.46 0.25 0.152.01 2.69 6.02 1.63 SLC2A13 Intron7 (NM_052885.1) rs10877835 SLC2A13Intron3 (NM_052885.1) 12 38,637,759 3.13 0.15 0.07 2.28 2.50 4.03 2.36rs11116586 SLC6A15 +106086bp (NM_182767.2), 12 83,650,812 3.08 0.73 0.621.68 2.48 2.41 1.27 SLC6A15 +127822bp (NM_018057.3) rs908440 TRHDE+374236bp (NM_013381.1) 12 71,719,925 3.11 0.73 0.62 1.69 2.48 3.10 1.95rs7485210 LOC116437 −10703bp (XM_378394) 12 130,163,733 3.19 0.57 0.451.64 2.46 2.66 1.59 rs10862927 SLC6A15 +113194bp (NM_182767.2), 1283,643,704 3.01 0.73 0.62 1.67 2.40 2.40 1.29 SLC6A15 +134930bp(NM_018057.3) rs4765680 CACNA1C Intron3 (NM_000719.3) 12 2,427,360 3.030.96 0.90 2.66 2.38 ND ND rs4643164 LOC122335 −355849bp (XM_063084) 13106,724,352 0.88 0.38 0.33 1.26 3.63 3.26 0.70 rs2802402 HTR2A −215185bp(NM_000621.1) 13 46,583,361 2.21 0.30 0.21 1.59 3.39 1.16 2.38rs17640758 DNAJD1 +11297bp (NM_013238.1) 13 42,590,879 2.16 0.14 0.081.91 3.07 0.00 2.48 rs2282267 CLMN Intron12 (NM_024734.2) 14 94,729,6483.75 0.69 0.55 1.76 3.33 3.22 1.59 rs2208986 SLC35F4 −84786bp(XM_292260) 14 57,218,154 0.82 0.76 0.71 1.26 3.29 0.70 0.33 rs4304940SLC35F4 −89221bp (XM_292260) 14 57,222,589 0.84 0.75 0.71 1.27 3.22 0.720.34 rs1028591 LOC283547 −65737bp (XM_378454) 14 38,495,490 0.43 0.640.61 1.14 3.20 0.82 0.39 rs7148801 AKAP6 Intron7 (NM_004274.3) 1432,206,647 3.68 0.95 0.88 2.80 3.18 2.11 0.64 rs3180753 CLMN Intron12(NM_024734.2) 14 94,729,500 3.64 0.68 0.55 1.74 3.11 3.01 1.53 rs2150324OR4L1 −2371bp (XM_063310) 14 19,595,673 0.29 0.54 0.52 1.10 3.07 1.110.49 rs10483416 AKAP6 Intron7 (NM_004274.3) 14 32,145,585 3.27 0.81 0.701.79 2.95 2.07 0.95 rs6571593 NPAS3 Intron2 (NM_022123.1), 14 32,865,5643.22 0.48 0.36 1.67 2.93 2.02 2.29 NPAS3 Intron3 (NM_173159.1) rs2282273CLMN Intron11 (NM_024734.2) 14 94,730,437 3.41 0.66 0.54 1.70 2.91 3.071.66

TABLE 45 High- Risk Allele High-Risk Fre- Allele quency Frequency OddsOdds in Pro- in Non- Critical Ratio Ratio Critical gressive pro- Oddsrate, (Homo- (Hetero- Chro- rate, Glau- gressive Ratio Geno- zygote)zygote) mo- Physical Allele coma Glaucoma (For- type (For- (For-DBSNP_ID Exon, Intron some Location (−logP) Group Group mula 6) (−logP)mula 7) mula 8) rs1622029 LOC283583 −1366892bp (XM_211092) 14 83,697,8043.52 0.71 0.58 1.74 2.83 3.23 2.07 rs8003168 RGS6 −36445bp (NM_004296.3)14 71,433,141 3.09 0.47 0.35 1.64 2.81 2.21 2.13 rs10498642 DICER1Intron9 (NM_030621.2), 14 94,658,292 3.42 0.62 0.49 1.68 2.80 2.91 1.97DICER1 Intron8 (NM_177438.1) rs9646147 LRFN5 −190930bp (NM_152447.2) 1440,956,160 3.19 0.92 0.84 2.19 2.76 ND ND rs1187627 CLMN Intron9(NM_024734.2) 14 94,734,482 3.50 0.59 0.46 1.69 2.75 2.82 1.79SNP_A-18219 MAMDC1-1035952bp (NM_182830.2) 14 47,918,097 3.37 0.59 0.471.67 2.72 2.68 1.38 rs14042 FLJ45244 Exon2 (NM_207443.1) 14 94,715,7733.38 0.56 0.43 1.67 2.72 2.86 1.70 rs1187626 CLMN Intron9 (NM_024734.2)14 94,735,610 3.38 0.60 0.47 1.68 2.71 2.88 1.80 rs1211448 CLMN Intron9(NM_024734.2) 14 94,734,970 3.28 0.59 0.46 1.66 2.60 2.74 1.82 rs848117SLC25A21 Intron3 (NM_030631.1) 14 36,326,610 3.15 0.12 0.05 2.62 2.43 ND2.34 rs12900219 NDN −100017bp (NM_002487.2) 15 21,583,560 3.84 0.93 0.852.46 3.79 1.48 0.48 rs2247154 TLE3 +105451bp (NM_005078.1) 15 68,024,0222.86 0.82 0.72 1.74 3.05 1.62 0.71 rs12324063 ATP10A Intron3(NM_024490.2) 15 23,540,049 3.60 0.43 0.30 1.74 2.82 2.80 1.82rs16941388 MYO1E −6977bp (NM_004998.1) 15 57,459,340 3.32 0.94 0.86 2.422.79 2.83 1.07 rs3863401 LRRC28 Intron6 (NM_144598.2) 15 97,698,743 3.590.61 0.48 1.71 2.79 2.85 1.66 rs12591327 TLN2 +69488bp (NM_015059.1) 1560,990,221 3.18 0.64 0.51 1.65 2.75 2.88 1.51 rs7173844 LRRC28 Intron6(NM_144598.2) 15 97,694,416 3.49 0.61 0.48 1.69 2.70 2.79 1.73 rs1717831NDN −95082bp (NM_002487.2) 15 21,578,625 3.06 0.90 0.82 2.03 2.51 2.451.10 rs4410020 MGC26690 −7119bp (NM_152450.1) 15 57,510,545 3.02 0.630.51 1.64 2.46 2.76 2.01 rs7198530 CHD9 −179353bp (NM_025134.2) 1651,641,067 1.00 0.17 0.13 1.40 3.77 0.00 2.13 rs9937509 CHD9 −162783bp(NM_025134.2) 16 51,657,637 1.00 0.18 0.14 1.39 3.74 0.00 2.11 rs436962CDH11 +25906bp (NM_001797.2), 16 63,512,280 1.68 0.84 0.77 1.54 3.730.71 0.28 CDH11 +25906bp (NM_033664.1) rs4309380 LOC440339 +245434bp(XM_498634) 16 13,523,196 3.83 0.32 0.20 1.89 3.47 2.73 2.23

TABLE 46 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs35146 CDH11 Intron12 (NM_001797.2), 16 63,541,382 2.24 0.86 0.79 1.703.43 0.76 0.31 CDH11 Intron12 (NM_033664.1) rs35572 LOC390735 −442487bp(XM_497515) 16 62,385,041 1.02 0.85 0.81 1.38 3.42 ND ND rs35165 CDH11+5537bp (NM_001797.2), 16 63,532,649 1.89 0.85 0.78 1.61 3.37 0.67 0.28CDH11 +5537bp (NM_033664.1) rs9302502 LOC440339 +251309bp (XM_498634) 1613,517,321 3.58 0.33 0.21 1.84 3.36 2.44 2.24 rs35192 CDH11 Intron4(NM_001797.2), 16 63,587,141 2.72 0.87 0.78 1.85 3.31 ND ND CDH11Intron4 (NM_033664.1) rs16968101 CDH11 +28144bp (NM_001797.2), 1663,510,042 1.89 0.86 0.79 1.61 3.30 0.67 0.28 CDH11 +28144bp(NM_033664.1) rs412474 CDH11 +15454bp (NM_001797.2), 16 63,522,732 2.150.86 0.79 1.68 3.28 0.76 0.32 CDH11 +15454bp (NM_033664.1) rs429065CDH11 +22043bp (NM_001797.2), 16 63,516,143 2.11 0.86 0.79 1.67 3.230.76 0.32 CDH11 +22043bp (NM_033664.1) rs1554401 CDH11 Intron4(NM_001797.2), 16 63,588,839 1.62 0.49 0.41 1.39 3.21 2.24 0.76 CDH11Intron4 (NM_033664.1) rs35162 CDH11 +5129bp (NM_001797.2), 16 63,533,0572.08 0.86 0.79 1.66 3.19 0.75 0.32 CDH11 +5129bp (NM_033664.1) rs35216CDH11 Intron8 (NM_001797.2), 16 63,572,992 2.08 0.86 0.79 1.66 3.15 0.770.33 CDH11 Intron8 (NM_033664.1) rs40116 CDH11 Intron8 (NM_001797.2), 1663,572,366 2.07 0.86 0.79 1.65 3.14 0.76 0.33 CDH11 Intron8(NM_033664.1) rs28216 CDH11 Exon7 (NM_001797.2), 16 63,579,615 2.07 0.860.79 1.65 3.14 0.76 0.33 CDH11 Exon7 (NM_033664.1)

TABLE 47 High-Risk High-Risk Allele Allele Odds Odds Frequency FrequencyCritical Ratio Ratio Critical in Pro- in Non- Odds rate, (Homo- (Hetero-Chro- rate, gressive progressive Ratio Geno- zygote) zygote) mo-Physical Allele Glaucoma Glaucoma (For- type (For- (For- DBSNP_ID Exon,Intron some Location (−logP) Group Group mula 6) (−logP) mula 7) mula 8)rs35140 CDH11 Intron11 (NM_001797.2), 16 63,548,272 2.03 0.86 0.79 1.643.12 0.75 0.32 CDH11 Intron11 (NM_033664.1) rs9925034 A2BP1 Intron2(NM_018723.2), 16 6,518,170 1.07 0.48 0.41 1.29 3.10 1.40 2.42 A2BP1−804582bp (NM_145891.1), A2BP1 −804582bp (NM_145892.1), A2BP1 −804582bp(NM_145893.1) rs460538 CDH11 +22417bp (NM_001797.2), 16 63,515,769 2.030.86 0.79 1.65 3.09 0.76 0.32 CDH11 +22417bp (NM_033664.1) rs1079008CDH11 Intron2 (NM_001797.2), 16 63,628,424 1.48 0.85 0.79 1.49 3.09 0.500.23 CDH11 Intron2 (NM_033664.1) rs35164 CDH11 +5484bp (NM_001797.2), 1663,532,702 1.99 0.86 0.79 1.64 3.08 0.74 0.32 CDH11 +5484bp(NM_033664.1) rs35214 CDH11 Intron8 (NM_001797.2), 16 63,573,409 2.020.86 0.79 1.64 3.08 0.76 0.33 CDH11 Intron8 (NM_033664.1) rs35200 CDH11Intron7 (NM_001797.2), 16 63,579,045 2.02 0.86 0.79 1.64 3.08 0.76 0.33CDH11 Intron7 (NM_033664.1) rs13333495 LOC440339 +265091bp (XM_498634)16 13,503,539 3.31 0.32 0.21 1.79 3.03 2.39 2.14 rs16962155 LOC440339+272794bp (XM_498634) 16 13,495,836 3.13 0.32 0.21 1.75 2.81 2.34 2.07rs6500718 A2BP1 −257472bp (NM_018723.2), 16 5,751,661 3.43 0.95 0.882.65 2.74 ND ND A2BP1 −1571091bp (NM_145891.1), A2BP1 −1571091bp(NM_145892.1), A2BP1 −1571091bp (NM_145893.1) rs12595090 LOC92017Intron9 (XM_042234) 16 12,378,613 3.07 0.51 0.39 1.63 2.52 2.69 1.30

TABLE 48 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs8062798 A2BP1 −253070bp (NM_018723.2), 16 5,756,063 3.02 0.95A2BP1 −1566689bp (NM_145891.1), A2BP1 −1566689bp (NM_145892.1), A2BP1−1.566689bp (NM_145893.1) rs1816581 CBLN1 +57699bp (NM_004352.1) 1647,812,497 3.26 0.41 rs1898359 CBLN1 +57192bp (NM_004352.1) 1647,813,004 3.26 0.41 rs9898312 SOCS3 +39255bp (NM_003955.3) 1773,825,204 0.49 0.54 rs231005 PMP22 +34074bp (NM_153322.1), 1715,039,748 2.71 0.69 PMP22 +34074bp (NM_153321.1), PMP22 +34074bp(NM_000304.2) rs10438771 BRIP1 +31746bp (NM_032043.1) 17 57,083,021 0.020.26 rs2074159 LGP2 Intron11 (NM_024119.1) 17 37,510,024 1.71 0.86rs4890199 RPH3AL +18823bp (NM_006987.2) 17 43,474 2.70 0.10 rs230923PMP22 +16078bp (NM_153322.1), 17 15,057,744 2.05 0.68 PMP22 +16078bp(NM_153321.1), PMP22 +16078bp (NM_000304.2) rs1553072 FLJ35773 +12632bp(NM_152599.2) 17 8,628,576 3.20 0.24 rs917593 MGC45562 Intron2(NM_152349.1) 17 36,070,052 3.08 0.30 rs17057804 LOC284274 −273821bp(XM_378756) 18 71,542,467 0.03 0.29 rs11872151 GTSCR1 −653277bp(XM_496277) 18 67,282,963 2.77 0.97 rs11150900 LOC284274 −284312bp(XM_378756) 18 71,552,958 0.37 0.67 rs1551434 GTSCR1 −637101bp(XM_496277) 18 67,266,787 3.59 0.95 rs8098925 LOC400655 −175143bp(XM_378753) 18 69,257,838 3.34 0.64 rs1828132 LOC284276 Intron2(XM_378757) 18 72,388,920 3.23 0.52 rs8088082 PPP4R1 −42712bp(NM_005134.1) 18 9,647,279 3.49 0.21 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype(Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP)(Formula 7) (Formula 8) rs8062798 0.89 2.50 2.38 ND ND rs1816581 0.291.70 2.35 2.66 1.60 rs1898359 0.29 1.70 2.35 2.66 1.60 rs9898312 0.501.15 3.67 1.43 2.74 rs231005 0.58 1.60 3.43 3.86 3.49 rs10438771 0.251.01 3.27 0.44 1.86 rs2074159 0.80 1.57 3.25 ND ND rs4890199 0.04 2.603.17 0.48 3.74 rs230923 0.59 1.50 3.06 3.63 3.58 rs1553072 0.14 1.932.60 6.76 1.70 rs917593 0.19 1.78 2.35 3.73 1.60 rs17057804 0.29 1.013.88 2.55 0.53 rs11872151 0.91 2.74 3.77 0.46 0.10 rs11150900 0.64 1.133.50 0.73 0.35 rs1551434 0.87 2.71 3.13 2.07 0.65 rs8098925 0.51 1.692.88 2.84 1.41 rs1828132 0.40 1.67 2.81 2.89 1.28 rs8088082 0.11 2.082.68 6.23 1.85

TABLE 49 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs2587428 CDH7 +60322bp (NM_033646.1), 18 61,759,477 3.15 0.50CDH7 +60323bp (NM_004361.2) rs6565975 LOC441825 +102358bp (XM_497596) 1873,316,910 3.19 0.75 rs10451358 ANKRD12 Intron7 (NM_015208.2) 189,207,471 3.05 0.43 rs1942583 LOC441825 +112581bp (XM_497596) 1873,327,133 3.02 0.72 rs12051936 LOC441825 +96235bp (XM_497596) 1873,310,787 3.11 0.60 rs4482359 LOC440479 +52521bp (XM_498693) 1810,180,764 3.16 0.64 rs12462868 FLJ36445 +22374bp (NM_153233.1) 1941,163,676 2.44 0.30 rs7260296 NTE +9039bp (NM_006702.2) 19 7,541,6890.57 0.62 rs1102152 KCTD15 +36141bp (NM_024076.1) 19 39,033,129 3.590.66 rs4802905 PPP2R1A Intron11 (NM_014225.3) 19 57,415,907 2.59 0.66rs734380 RPS5 Intron1 (NM_001009.2) 19 63,590,775 2.85 0.52 rs1072678ZNF600 +14950bp (NM_198457.1) 19 57,944,329 3.53 0.14 rs734379 RPS5Intron1 (NM_001009.2) 19 63,590,994 3.11 0.61 rs6132862 LOC400840+29346bp (XM_375912) 20 25,669,248 3.95 0.37 rs4572656 PTPRT +22230bp(NM_007050.3), 20 40,112,577 3.60 0.89 PTPRT +22230bp (NM_133170.1)rs119416 KCNB1 Intron1 (NM_004975.2) 20 47,469,004 3.98 0.70 rs6019825KCNB1 Intron1 (NM_004975.2) 20 47,472,824 3.55 0.56 rs6045666 PDYN+18899bp (NM_024411.2) 20 1,888,504 3.67 0.34 rs6138601 KIAA0980−32244bp (NM_025176.3) 20 25,487,486 3.69 0.39 rs6035140 PTPNS1 +15755bp(NM_080792.1) 20 1,884,292 3.67 0.35 rs12480036 CHD6 Intron1(NM_032221.3) 20 39,629,243 3.84 0.80 rs6138598 KIAA0980 −6294bp(NM_025176.3) 20 25,461,536 3.44 0.38 rs517578 SIRPB2 −50868bp(NM_018556.2), 20 1,637,270 3.30 0.42 SIRPB2 −50868bp (NM_080816.1)High-Risk Allele Frequency in Critical rate, Odds Ratio Odds RatioNonprogressive Odds Ratio Genotype (Homozygote) (Heterozygote) DBSNP_IDGlaucoma Group (Formula 6) (−logP) (Formula 7) (Formula 8) rs25874280.38 1.64 2.60 2.56 1.91 rs6565975 0.63 1.71 2.57 3.30 2.24 rs104513580.31 1.65 2.54 3.05 1.32 rs1942583 0.61 1.66 2.42 3.03 2.17 rs120519360.47 1.63 2.33 2.56 1.70 rs4482359 0.51 1.66 2.30 2.51 1.46 rs124628680.21 1.64 3.69 11.93 1.05 rs7260296 0.58 1.18 3.37 1.89 3.13 rs11021520.53 1.73 3.18 2.64 2.56 rs4802905 0.55 1.58 3.13 2.04 0.85 rs7343800.41 1.59 3.11 2.72 2.35 rs1072678 0.06 2.59 2.92 ND 2.53 rs734379 0.491.63 2.86 3.24 1.95 rs6132862 0.24 1.86 3.67 2.58 2.31 rs4572656 0.792.08 3.41 1.95 0.77 rs119416 0.56 1.79 3.40 3.04 1.48 rs6019825 0.431.70 3.29 3.06 1.30 rs6045666 0.22 1.85 3.28 2.73 2.16 rs6138601 0.261.80 3.23 2.64 2.11 rs6035140 0.23 1.83 3.14 2.65 2.09 rs12480036 0.691.89 3.13 4.18 2.36 rs6138598 0.26 1.76 3.11 2.45 2.13 rs517578 0.301.70 3.11 2.38 2.16

TABLE 50 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs2050223 C20orf23 +550936bp (NM_024704.3) 20 15,649,814 1.97 0.65rs926663 MAFB +68744bp (NM_005461.3) 20 38,679,189 2.89 0.47 rs6072407CHD6 Intron2 (NM_032221.3) 20 39,596,216 3.83 0.82 rs6138532 ENTPD6−5585bp (NM_001247.1) 20 25,118,787 3.00 0.45 rs6083320 CST5 −31324bp(NM_001900.2) 20 23,839,641 3.26 0.41 rs2076147 ZHX3 Exon4 (NM_015035.2)20 39,246,420 3.68 0.50 rs1857051 CST5 −33523bp (NM_001900.2) 2023,841,840 3.35 0.50 rs4810317 CHD6 +8124bp (NM_032221.3) 20 39,456,4603.54 0.81 rs6089908 KCNQ2 Intron10 (NM_004518.2), 20 61,519,098 3.330.90 KCNQ2 Intron11 (NM_172106.1), KCNQ2 Intron12 (NM_172107.1), KCNQ2Intron11 (NM_172108.1), KCNQ2 +16378bp (NM 172109.1) rs6095508 KCNB1Intron1 (NM_004975.2) 20 47,461,578 3.30 0.58 rs4812180 LOC284757+371993bp (XM_496478) 20 58,704,985 3.73 0.09 rs6115458 FLJ38374−66026bp (NM_182583.1) 20 25,917,265 3.19 0.38 rs1321001 CDH22 Intron7(NM_021248.1) 20 44,250,143 3.08 0.64 rs3761258 C20orf45 −727bp(NM_016045.1) 20 57,051,991 3.08 0.97 rs94967 LOC150084 +21299bp(XM_086761) 21 40,117,177 3.96 0.78 rs4816657 LOC150084 Intron4(XM_086761) 21 40,068,705 3.77 0.77 rs2837211 LOC150084 Intron4(XM_086761) 21 40,070,264 3.64 0.77 rs1018350 LOC150084 Intron4(XM_086761) 21 40,070,715 3.64 0.77 rs463903 LOC150084 Intron8(XM_086761) 21 40,087,547 3.51 0.77 rs2837248 PCP4 −19612bp(NM_006198.1) 21 40,141,638 3.50 0.67 rs2178882 LOC150084 Intron5(XM_086761) 21 40,075,682 3.44 0.77 High-Risk Allele Frequency inCritical rate, Odds Ratio Odds Ratio Nonprogressive Odds Ratio Genotype(Homozygote) (Heterozygote) DBSNP_ID Glaucoma Group (Formula 6) (−logP)(Formula 7) (Formula 8) rs2050223 0.56 1.46 3.08 1.66 0.70 rs926663 0.351.61 3.08 2.29 2.27 rs6072407 0.71 1.92 3.07 4.47 2.58 rs6138532 0.331.66 3.04 2.44 2.24 rs6083320 0.29 1.70 3.02 4.16 1.53 rs2076147 0.371.72 3.01 2.99 1.82 rs1857051 0.38 1.68 2.90 3.22 1.65 rs4810317 0.701.85 2.89 3.27 1.68 rs6089908 0.81 2.16 2.76 2.60 1.09 rs6095508 0.451.67 2.74 2.94 1.83 rs4812180 0.03 3.77 2.72 ND 3.14 rs6115458 0.26 1.712.51 2.56 1.84 rs1321001 0.51 1.65 2.47 2.84 1.74 rs3761258 0.92 3.072.44 ND ND rs94967 0.65 1.88 3.72 5.80 3.59 rs4816657 0.65 1.83 3.073.69 2.12 rs2837211 0.65 1.80 2.96 3.66 2.14 rs1018350 0.65 1.80 2.963.66 2.14 rs463903 0.65 1.78 2.86 3.63 2.17 rs2837248 0.55 1.71 2.833.10 1.94 rs2178882 0.65 1.80 2.73 3.61 2.20

TABLE 51 High-Risk Allele Critical rate, Frequency in Physical AlleleProgressive DBSNP_ID Exon, Intron Chromosome Location (−logP) GlaucomaGroup rs4816658 LOC150084 Intron5 (XM_086761) 21 40,075,924 3.53 0.77rs458406 LOC150084 Intron8 (XM_086761) 21 40,089,698 3.32 0.77 rs2837220LOC150084 Intron6 (XM_086761) 21 40,082,808 3.39 0.73 rs12627261LOC150084 Intron6 (XM_086761) 21 40,085,416 3.39 0.73 rs1571713LOC150084 Intron6 (XM_086761) 21 40,075,065 3.32 0.77 rs2826774 NCAM2Intron5 (NM_004540.2) 21 21,588,847 3.34 0.60 rs465258 LOC150084 Intron8(XM_086761) 21 40,093,614 3.22 0.76 rs369977 LOC388814 +131764bp(XM_373926) 21 15,532,948 3.02 0.68 rs5750009 LOC402059 Intron8(XM_497817) 22 33,679,879 2.13 0.81 rs1013513 LOC402059 Intron8(XM_497817) 22 33,678,294 2.12 0.81 rs5999654 LOC402059 Intron8(XM_497817) 22 33,682,537 2.12 0.81 rs1139056 CECR1 Exon7 (NM_177405.1),22 16,035,732 3.28 0.26 CECR1 Ezon9 (NM_017424.2) rs5759839 LOC388882Intron4 (XM_371455) 22 22,141,794 3.04 0.59 High-Risk Allele Frequencyin Critical rate, Odds Ratio Odds Ratio Nonprogressive Odds RatioGenotype (Homozygote) (Hetrozygote) DBSNP_ID Glaucoma Group (Formula 6)(−logP) (Formula 7) (Formula 8) rs4816658 0.65 1.82 2.72 3.32 1.92rs458406 0.65 1.75 2.69 3.46 2.07 rs2837220 0.61 1.73 2.65 2.91 1.67rs12627261 0.61 1.73 2.65 2.91 1.67 rs1571713 0.65 1.76 2.65 3.38 1.99rs2826774 0.47 1.68 2.62 2.81 1.71 rs465258 0.65 1.73 2.62 3.45 2.10rs369977 0.57 1.64 2.37 2.50 1.39 rs5750009 0.73 1.58 3.68 12.15 11.55rs1013513 0.73 1.58 3.43 11.57 10.59 rs5999654 0.73 1.58 3.43 11.5710.59 rs1139056 0.15 1.90 2.50 3.23 1.91 rs5759839 0.47 1.62 2.36 2.611.55

Tables 29 to 51 list dbSNP ID number or Affimetrix Array ID numberspecifying known single nucleotide polymorphisms obtained, the exon,intron information (in a case where a single nucleotide polymorphismexists on a gene, the gene name and the exon or intron in which SNPexists are shown, and in a case where a single nucleotide polymorphismdoes not exist on a gene, neighboring genes and a distance between thegene and the single nucleotide polymorphism are shown), the chromosomenumber at which the single nucleotide polymorphism exists, the physicallocation of the single nucleotide polymorphism, the p-value for anallele according to a chi-square test (−log P), the high-risk allelefrequencies in the progressive glaucoma group and the nonprogressiveglaucoma group, the odds ratio for an allele, the p-value for a genotypeaccording to a chi-square test (−log P), the odds ratio for a genotypeof a homozygote, and the odds ratio for a genotype of a heterozygote.Here, in the tables, a portion of which odds ratio is indicated as NDshows a case where any one of the number of detection in the denominatoris 0, so that the odds ratio could not be calculated.

According to the above studies, 480 single nucleotide polymorphisms ofwhich alleles or genotypes were associated with the progression ofglaucoma at a p-value of 1×10⁻³ or less were found.

When the allele or genotype frequencies listed in Tables 29 to 51 werecompared between the progressive glaucoma cases and the nonprogressiveglaucoma cases, a statistical difference was found. By determining anallele of any one of these single nucleotide polymorphisms, whether ornot an allele that is identified in a higher frequency in theprogressive glaucoma group than that of the nonprogressive glaucomagroup exists in the sample can be determined.

Example 5 Confirmation of Novel Single Nucleotide Polymorphisms bySequencing Method of Surrounding of Specified Single NucleotidePolymorphisms

Surrounding sequences of single nucleotide polymorphisms described inTables 1 to 2 or Tables 26 to 28 are subjected to re-sequencing, so thatthe detection of a single nucleotide polymorphism can be confirmed, andthat an unknown single nucleotide polymorphism that possibly exists canbe identified. The re-sequencing can be performed according to any knownmethods, and for example, the re-sequencing can be performed by a directsequencing method.

Example 6

In order to determine the single nucleotide polymorphisms associatedwith glaucoma identified in Example 3 or 4, or the alleles and genotypesof known single nucleotide polymorphisms existing in the surroundingsequences of the single nucleotide polymorphisms listed in Tables 1 to51, an immobilized probe can be prepared. A known single nucleotidepolymorphism can be referred to, for example, the database of dbSNP or JSNP. In the immobilized probe, for example, an oligonucleotide probedesigned so as to maximize its sensitivity, specificity orreproducibility for several probes to several hundred-thousand probescan be loaded. The immobilized probe can be produced according to amethod such as a method of synthesizing an oligonucleotide on a solidcarrier or a method including the steps of previously synthesizing anoligonucleotide and immobilizing the oligonucleotide in a high densityon a solid carrier.

Example 7

The presence or the absence of the onset of glaucoma can be determinedat a more accurate level using the immobilized probe produced in Example6. A probe for detecting a single nucleotide polymorphism associatedwith a disease is plurally combined, so that the level of which theonset risk of glaucoma increases is evaluated. In a case where a valueexceeds a threshold, it is determined that the onset of glaucoma takesplace.

In addition, using the immobilized probe produced in Example 6, thesingle nucleotide polymorphism existing on the genome of the glaucomapatients and that of the non-glaucoma patients can be compared. There isa possibility that single nucleotide polymorphisms existing in locationswith an adjacent distance to each other are linked and inherited bylinkage disequilibrium. There is a possibility that single nucleotidepolymorphisms linked with the single nucleotide polymorphisms listed inTables 1 and 2 or Tables 26 to 28 can be identified by the immobilizedprobe, so that it can be expected that a single nucleotide polymorphismhaving an even stronger association with glaucoma is found.

Example 8 Design of Custom Array

In order to maintain a statistical power while lowering type I error,candidate single nucleotide polymorphisms associated with the onset ofglaucoma identified in the primary analysis of Example 3 were subjectedto a secondary analysis of a single nucleotide polymorphism inseparately collected samples using an array for analyzing a singlenucleotide polymorphism designed in an original style (hereinafter,referred to as a custom array).

For the custom array, a kit for analyzing a single nucleotidepolymorphism commercially available from Illumina [Illumina, iSelect™Genotyping BeadChip] was used. For 446 single nucleotide polymorphismsassociated with the onset of glaucoma showing a p-value of 1×10⁻³ orless in Example 3, the designing of a probe for specifically detectingthese single nucleotide polymorphisms was tried. Since these probes arerandomly immobilized to the substrate via beads, the step of specifyinga location of the beads (decoding) is needed. A probe for detecting asingle nucleotide polymorphism of which location was unable to bespecified in a process of decoding was excluded from the subject foranalysis. As a result, the preparation of a custom array capable oftyping 412 single nucleotide polymorphisms out of 446 single nucleotidepolymorphisms is made possible, and the custom array was used in theanalysis of a single nucleotide polymorphism described later. Here, asdescribed in the section of Infinium (registered trademark) assay in abeads-array method, in these assay methods, there are two methods, i.e.a method using one kind of a probe and a method using two kinds ofprobes. Basically, in the detection of one single nucleotidepolymorphism, one kind of the probe was used, and two probes were usedfor some single nucleotide polymorphisms.

Example 9 Analysis of Single Nucleotide Polymorphism Using Custom Array

The experiment was performed in accordance with the instruction manualsof the custom array kit and the analyzing instrument of Illumina, usingspecialized reagents contained in the kit. Briefly, the experimentalprocedures will be explained as follows. A reagent specialized in thetreatment of the genome and a sodium hydroxide solution were added to150 to 300 ng of the total DNA extracted in Example 1. Next, an enzymefor amplifying a whole genome was added thereto, and the mixture wasincubated at 37° C. for 20 to 24 hours, and a whole genome wasamplified. Further, an enzyme for fragmentation was added thereto, andthe mixture was incubated at 37° C. for one hour. After the DNA wasprecipitated with isopropanol, a reagent for solubilization was added tothe precipitates, and the mixture was suspended at 48° C. for one hour.A mixture was heat-denatured at 95° C. for 20 minutes, and this solutionwas injected into the custom array, and hybridization was carried out at48° C. for 16 to 24 hours.

After the hybridization, an allele-specific extension reaction or asingle base extension reaction was performed for each probe, and thefluorescent signals were amplified. The signals were read with a scanner(Illumina, BeadArray Reader) compatible to the kit. In addition, aspecialized software (Illumina, BeadStudio 3.1) was used in the analysisof the single nucleotide polymorphisms. According to the presentanalytical method, the opposite alleles of a single nucleotidepolymorphism can be determined simultaneously, and the genotypes weredetermined on the basis of the analytical results. The genotype wasdetermined to be a heterozygote when both the signals of each of thealleles constituting a single nucleotide polymorphism were detected, andthe genotype was determined to be a homozygote of the detected allelewhen only one of the signals of the alleles was detected.

The precision of the determination of a genotype was confirmed for allthe single nucleotide polymorphisms to be analyzed on the basis of acluster image showing a distribution of fluorescent signals, inaccordance with Infinium (registered trademark) Genotyping DataAnalysis, an analyzing manual of Illumina. The genotypes of the singlenucleotide polymorphisms that are determined accurately are indicated onthe image as three clusters of fluorescent signals that are completelyseparated from each other (two kinds of homozygotes and a heterozygote).

On the other hand, boundary lines of the three clusters become unclearfor the single nucleotide polymorphisms that are not determinedaccurately. In a case where a degree of separation of the clusters isdetermined not to be high according to analysis software, the clusterimage of the single nucleotide polymorphism was reconfirmed. In a casewhere a genotype was determined regardless of unclearness of theclusters, the sample was excluded from the subsequent analyticaloperations. Here, the confirmation of the cluster image was carried outunder masking, in other words, in a state that the names of singlenucleotide polymorphisms and p-values could not be compared with thesingle nucleotide polymorphisms. Here, the single nucleotidepolymorphisms overlapping between the custom array used in the secondaryanalysis and GeneChip Human Mapping 500K of Affimetrix used in theprimary analysis showed a concordance rate of 99% or more, when theconcordance rates of the determination of genotypes were compared using104 samples.

Example 10 Determination of Genotypes in Glaucoma Patients andNon-Patients

Primary open-angle glaucoma patients and normal tension glaucomapatients diagnosed on the basis of Guidelines offered by Japan GlaucomaSociety were assigned to a glaucoma patient group, and healthyindividuals confirmed to have no family history of glaucoma according toa medical interview were assigned to a non-patient group. For thepresent analysis, the same samples used in Example 3 for performing theprimary analysis were not used, and new samples were collected. Blooddonated under the consent on free will of the participants after havingsufficiently explained the contents of studies from 409 cases of theglaucoma patient group and 448 controls of the non-patient group, eachgroup being different from those of Example 3 was used as a specimen, atotal DNA was extracted according to the method described in Example 1,and the analysis of single nucleotide polymorphisms was performedaccording to the method described in Example 9. The analytical resultsof a single nucleotide polymorphism obtained in each of the patientswere stored in the Laboratory Information Management System (WorldFusion, LaboServer) adopting a relational database. A specializedanalysis program for a single nucleotide polymorphism was created andloaded within the system, and the analysis described as follows wasperformed. In detail, a single nucleotide polymorphism considered tohave a high experimental reliability was extracted by rejecting a singlenucleotide polymorphism having a call rate of less than 90% in both theglaucoma patient group and the non-patient group, and a singlenucleotide polymorphism having a minor allele frequency of less than 5%.

Example 11 Meta-Analysis

In a meta-analysis, the Mantel-Haenszel method was used (WakariyasuiIgaku Tokeigaku (Easy Medical Statistics), pp. 48-80, Toshio

MORIZANE, Medical Tribune). In detail, 402 single nucleotidepolymorphisms considered to have a high experimental reliability in bothof the methods described in Example 3 and Example 10 were subjected tostatistical comparisons of the allele frequency and two genotypefrequencies (a dominant genetic model and a recessive genetic model)using Mantel-Haenszel chi-square test. Single nucleotide polymorphismsof which any one of an allele model, a dominant genetic model, and arecessive genetic model shows association with the onset of glaucoma ata p-value of 1.2×10⁻⁴ or less (the level of Bonferroni correctioncorresponding to p<5×10⁻² when 402 times of multiple comparisons wereperformed), that is, −log P of 3.91 or more, are listed in Table 52.

The calculations of the Mantel-Haenszel chi-square test, and the oddsratio in the Mantel-Haenszel method for these single nucleotidepolymorphisms, and a 95% confidence interval were performed according tothe following procedures.

A Mantel-Haenszel chi-square value was determined for the allele model,the dominant genetic model, and the recessive genetic model, and ap-value was calculated by comparing the value with the chi-squaredistribution of a degree of freedom of 1.

The Mantel-Haenszel chi-square value (λA_(MH) ²) of the allele model wascalculated according to the following formulas.

EA_(i) = xA_(i)mA_(i)/NA_(i)${VA}_{i} = \frac{{mA}_{i}{nA}_{i}{xA}_{i}{yA}_{i}}{{NA}_{i}^{2}\left( {{NA}_{i} - 1} \right)}$${\chi A}_{MH}^{2} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hA}_{i} - {EA}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VA}_{i}}$

-   -   xA_(i): a total number of detection of a high-risk allele,    -   yA_(i): a total number of detection of a low-risk allele,    -   mA_(i): a total number of detection of alleles in the glaucoma        patient group,    -   nA_(i): a total number of detection of alleles in the        non-patient group,    -   NA_(i): a total number of detection of alleles, and    -   hA_(i): the number of detection of a high-risk allele in the        glaucoma patient group.

The Mantel-Haenszel chi-square value (χD_(MH) ²) of the dominant geneticmodel was calculated according to the following formulas.

ED_(i) = xD_(i)mD_(i)/ND_(i)${VD}_{i} = \frac{{mD}_{i}{nD}_{i}{xD}_{i}{yD}_{i}}{{ND}_{i}^{2}\left( {{ND}_{i} - 1} \right)}$${\chi D}_{MH}^{2} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hD}_{i} - {ED}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VD}_{i}}$

-   -   xD_(i): the sum of a total number of detection of a homozygote        of a high-risk allele and a total number of detection of a        heterozygote,    -   yD_(i): a total number of detection of a homozygote of a        low-risk allele,    -   mD_(i): a total number of detection of genotypes in the glaucoma        patient group,    -   nD_(i): a total number of detection of genotypes in the        non-patient group,    -   ND_(i): a total number of detection of genotypes, and    -   hD_(i): the sum of the number of detection of a homozygote of a        high-risk allele and the number of detection of a heterozygote        in the glaucoma patient group.

The Mantel-Haenszel chi-square value (χR_(MH) ²) of the recessivegenetic model was calculated according to the following formulas.

ER_(i) = xR_(i)mR_(i)/NR_(i)${VR}_{i} = \frac{{mR}_{i}{nR}_{i}{xR}_{i}{yR}_{i}}{{NR}_{i}^{2}\left( {{NR}_{i} - 1} \right)}$${\chi R}_{MH}^{2} = \frac{\left\lbrack {{{\sum\limits_{i = 1}^{k}\left( {{hR}_{i} - {ER}_{i}} \right)}} - 0.5} \right\rbrack^{2}}{\sum\limits_{i = 1}^{k}{VR}_{i}}$

-   -   xR_(i): a total number of detection of a homozygote of a        high-risk allele,    -   yR_(i): the sum of a total number of detection of a homozygote        of a low-risk allele and a total number of detection of a        heterozygote of a genotype,    -   mR_(i): a total number of detection of genotypes in the glaucoma        patient group,    -   nR_(i): a total number of detection of genotypes in the        non-patient group,    -   NR_(i): a total number of detection of genotypes, and    -   hR_(i): the number of detection of a homozygote of a high-risk        allele in the glaucoma patient group.

The odds ratio in the Mantel-Haenszel test was calculated for the allelemodel, the dominant genetic model, and the recessive genetic model.

The odds ratio in the Mantel-Haenszel test (ORa_(a) _(H)) for the allelemodel was calculated according to the following formula.

${ORa}_{MH} = \frac{{\sum\limits_{i = 1}^{k}\; {{Aa}_{i}{{Da}_{i}/{Za}_{i}}}}\;}{\sum\limits_{i = 1}^{k}{{Ba}_{i}{{Ca}_{i}/{Za}_{i}}}}$

-   -   Aa_(i): the number of detection of a high-risk allele in the        glaucoma patient group,    -   Ba_(i): the number of detection of a low-risk allele in the        glaucoma patient group,    -   Ca_(i): the number of detection of a high-risk allele in the        non-patient group,    -   Da_(i): the number of detection of a low-risk allele in the        non-patient group, and    -   Za_(i): a total number of detection of alleles.

The odds ratio in the Mantel-Haenszel test (ORd_(MH)) for the dominantgenetic model was calculated according to the following formula.

${ORd}_{MH} = \frac{{\sum\limits_{i = 1}^{k}{{Ad}_{i}{{Dd}_{i}/{Zd}_{i}}}}\;}{\sum\limits_{i = 1}^{k}{{Bd}_{i}{{Cd}_{i}/{Zd}_{i}}}}$

-   -   Ad_(i): the sum of the number of detection of a homozygote of a        high-risk allele in the glaucoma patient group and the number of        detection of a heterozygote in the glaucoma patient group,    -   Bd_(i): the number of detection of a homozygote of a low-risk        allele in the glaucoma patient group,    -   Cd_(i): the sum of the number of detection of a homozygote of a        high-risk allele in the non-patient group and the number of        detection of a heterozygote in the non-patient group,    -   Dd_(i): the number of detection of a homozygote of a low-risk        allele in the non-patient group, and    -   Zd_(i): a total number of detection of genotypes.

The odds ratio in the Mantel-Haenszel test (ORr_(MH)) for the recessivegenetic model was calculated according to the following formula.

${ORr}_{MH} = \frac{{\sum\limits_{i = 1}^{k}{{Ar}_{i}{{Dr}_{i}/{Zr}_{i}}}}\;}{\sum\limits_{i = 1}^{k}{{Br}_{i}{{Cr}_{i}/{Zr}_{i}}}}$

-   -   Ar_(i): the number of detection of a homozygote of a high-risk        allele in the glaucoma patient group,    -   Br_(i): the sum of the number of detection of a heterozygote in        the glaucoma patient group and the number of detection of a        homozygote of a low-risk allele in the glaucoma patient group,    -   Cr_(i): the number of detection of a homozygote of a high-risk        allele in the non-patient group,    -   Dr_(i): the sum of the number of detection of a heterozygote in        the non-patient group and the number of detection of a        homozygote of a low-risk allele in the non-patient group, and    -   Zr_(i): a total number of detection of genotypes.

A 95% confidence interval of the odds ratio in the Mantel-Haenszel testwas calculated for the allele model, the dominant genetic model, and therecessive genetic model.

The 95% confidence interval (95% CI_(A)) for the allele model wascalculated according to the following formulas.

${{PA}_{i} = \frac{{aA}_{i} + {dA}_{i}}{{zA}_{i}}},{{QAi} = \frac{{bA}_{i} + {cA}_{i}}{{zA}_{i}}},{{RA}_{i} = \frac{{aA}_{i}{dA}_{i}}{{zA}_{i}}},{{SA}_{i} = \frac{{bA}_{i}{cA}_{i}}{{zA}_{i}}}$${VarA} = {\frac{\sum\limits_{i = 1}^{k}{{PA}_{i}{RA}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RA}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PA}_{i}{SA}_{i}} + {{QA}_{i}{RA}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RA}_{i}{\sum\limits_{i = 1}^{k}{SA}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QA}_{i}{SA}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SA}_{i}} \right)^{2}}}$${95\% \mspace{14mu} {CI}_{A}} = {\exp \left( {{\log {ORa}}_{MH} \pm {1.96\sqrt{VarA}}} \right)}$

-   -   aA_(i): the number of detection of a high-risk allele in the        glaucoma patient group,    -   bA_(i): the number of detection of a low-risk allele in the        glaucoma patient group,    -   cA_(i): the number of detection of a high-risk allele in the        non-patient group,    -   dA_(i): the number of detection of a low-risk allele in the        non-patient group,    -   zA_(i): a total number of detection of alleles, and    -   ORa_(MH): an odds ratio in Mantel-Haenszel test for an allele        model.

A 95% confidence interval (95% CI_(d)) for the dominant genetic modelwas calculated according to the following formulas.

${{PD}_{i} = \frac{{aD}_{i} + {dD}_{i}}{{zD}_{i}}},{{QDi} = \frac{{bD}_{i} + {cD}_{i}}{{zD}_{i}}},{{RD}_{i} = \frac{{aD}_{i}{dD}_{i}}{{zD}_{i}}},{{SD}_{i} = \frac{{bD}_{i}{cD}_{i}}{{zD}_{i}}}$${VarD} = {\frac{\sum\limits_{i = 1}^{k}{{PD}_{i}{RD}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RD}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PD}_{i}{SD}_{i}} + {{QD}_{i}{RD}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RD}_{i}{\sum\limits_{i = 1}^{k}{SD}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QD}_{i}{SD}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SD}_{i}} \right)^{2}}}$${95\% \mspace{14mu} {CI}_{d}} = {\exp \left( {{\log {ORd}}_{MH} \pm {1.96\sqrt{VarD}}} \right)}$

-   -   aD_(i): the sum of the number of detection of a homozygote of a        high-risk allele in the glaucoma patient group and the number of        detection of a heterozygote in the glaucoma patient group,    -   bD_(i): the number of detection of a homozygote of a low-risk        allele in the glaucoma patient group,    -   cD_(i): the sum of the number of detection of a homozygote of a        high-risk allele in the non-patient group and the number of        detection of a heterozygote in the non-patient group,    -   dD_(i): the number of detection of a homozygote of a low-risk        allele in the non-patient group,    -   zD_(i): a total number of detection of genotypes, and    -   ORd_(MH): an odds ratio in Mantel-Haenszel test for a dominant        genetic model.

A 95% confidence interval (95% CI_(r)) for the recessive genetic modelwas calculated according to the following formulas.

${{PR}_{i} = \frac{{aR}_{i} + {dR}_{i}}{{zR}_{i}}},{{QRi} = \frac{{bR}_{i} + {cR}_{i}}{{zR}_{i}}},{{RR}_{i} = \frac{{aR}_{i}{dR}_{i}}{{zR}_{i}}},{{SR}_{i} = \frac{{bR}_{i}{cR}_{i}}{{zR}_{i}}}$${VarR} = {\frac{\sum\limits_{i = 1}^{k}{{PR}_{i}{RR}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{RR}_{i}} \right)} + \frac{\sum\limits_{i = 1}^{k}\left( {{{PR}_{i}{SR}_{i}} + {{QR}_{i}{RR}_{i}}} \right)}{2{\sum\limits_{i = 1}^{k}{{RR}_{i}{\sum\limits_{i = 1}^{k}{SR}_{i}}}}} + \frac{\sum\limits_{i = 1}^{k}{{QR}_{i}{SR}_{i}}}{2\left( {\sum\limits_{i = 1}^{k}{SR}_{i}} \right)^{2}}}$${95\% \mspace{14mu} {CI}_{r}} = {\exp \left( {{\log {ORr}}_{MH} \pm {1.96\sqrt{VarR}}} \right)}$

-   -   aR_(i): the number of detection of a homozygote of a high-risk        allele in the glaucoma patient group,    -   bR_(i): the sum of the number of detection of a heterozygote in        the glaucoma patient group and the number of detection of a        homozygote of a low-risk allele in the glaucoma patient group,    -   cR_(i): the number of detection of a homozygote of a high-risk        allele in the non-patient group,    -   dR_(i): the sum of the number of detection of a heterozygote in        the non-patient group and the number of detection of a        homozygote of a low-risk allele in the non-patient group,    -   zR_(i): a total number of detection of genotypes, and    -   ORr_(MH): an odds ratio in Mantel-Haenszel test for a recessive        genetic model.

TABLE 52 High-Risk Allele High- Frequency in Physical Linkage RiskGlaucoma dBSNP ID Chromosome Location Exon, Intron Disequilibrium Allele1 Allele 2 Allele Patient Group rs4516662 4 140,178,445 CCRN4L −116103bp(NM_012118.2) LD1 C G C 0.56 rs13110551 4 140,178,323 CCRN4L −116225bp(NM_012118.2) LD1 A G G 0.58 rs11123034 2 124,776,617 CNTNAP5 Intron3(NM_130773.2), LD2 A G G 0.59 CNTNAP5 Intron3 (NM_138996.1) rs12611812 2124,776,344 CNTNAP5 Intron3 (NM_130773.2), LD2 A T A 0.59 CNTNAP5Intron3 (NM_138996.1) rs7961953 12 81,594,304 DKFZp762A217 Intron1(NM_152588.1) A G A 0.33 rs6451268 5 36,291,121 FLJ25422 Intron11(NM_145000.2) A G G 0.62 rs7559118 2 133,706,762 FLJ34870 Intron4(NM_207481.1) A G G 0.64 rs7850541 9 133,080,108 GBGT1 −11253bp(NM_021996.3) A G G 0.78 rs9358578 6 22,810,626 LOC389370 Intron(XM_374162) A G A 0.45 rs16935718 8 70,265,525 LOC389667 +60391bp(XM_372046) LD3 A G A 0.74 rs16935744 8 70,280,548 LOC389667 +75414bp(XM_372046) LD3 A C C 0.74 rs705998 8 70,295,144 LOC389667 +90010bp(XM_372046) LD3 A G G 0.71 rs10517556 4 62,947,647 LOC391656 −135832bp(XM_373027) A G G 0.51 rs7081455 10 20,678,891 PLXDC2 +69770bp(NM_032812.7) A C A 0.83 rs547984 1 234,422,927 ZP4 −42951bp(NM_021186.2) LD4 A C A 0.54 rs540782 1 234,423,080 ZP4 −43104bp(NM_021186.2) LD4 C G G 0.54 rs693421 1 234,525,131 ZP4 −45155bp(NM_021186.2) LD4 A C A 0.53 rs2499601 1 234,430,936 ZP4 −50960bp(NM_021186.2) LD4 A G G 0.53 High-Risk Allele Mantel- Mantel- Frequencyin Haenszel Haenszel 95% Sequence Sequence Sequence 1 for Sequence 2 forNon-Patient Test Test Odds Confidence Containing Containing SecondarySecondary dBSNP ID Group P-value Model Ratio Interval Allele 1 Allele 2Analysis Probe Analysis Probe rs4516662 0.51 0.000021 Dominant 1.71.4-2.3 SEQ ID No: 203 SEQ ID No: 204 SEQ ID No: 515 SEQ ID No: 533rs13110551 0.52 0.000004 Dominant 1.9 1.4-2.4 SEQ ID No: 205 SEQ ID No:206 SEQ ID No: 516 rs11123034 0.54 0.000074 Recessive 1.6 1.2-1.9 SEQ IDNo: 207 SEQ ID No: 208 SEQ ID No: 517 rs12611812 0.54 0.000074 Recessive1.6 1.2-1.9 SEQ ID No: 209 SEQ ID No: 210 SEQ ID No: 518 SEQ ID No: 534rs7961953 0.26 0.000067 Allele 1.4 1.2-1.6 SEQ ID No: 211 SEQ ID No: 212SEQ ID No: 519 rs6451268 0.58 0.000072 Dominant 1.8 1.3-2.3 SEQ ID No:213 SEQ ID No: 214 SEQ ID No: 520 rs7559118 0.58 0.000005 Dominant 1.91.4-2.5 SEQ ID No: 215 SEQ ID No: 216 SEQ ID No: 521 rs7850541 0.720.000109 Allele 1.4 1.2-1.6 SEQ ID No: 217 SEQ ID No: 218 SEQ ID No: 522rs9358578 0.38 0.000106 Allele 1.3 1.2-1.5 SEQ ID No: 219 SEQ ID No: 220SEQ ID No: 523 rs16935718 0.68 0.000017 Dominant 2.4 1.6-3.5 SEQ ID No:221 SEQ ID No: 222 SEQ ID No: 524 rs16935744 0.68 0.000024 Dominant 2.31.6-3.4 SEQ ID No: 223 SEQ ID No: 224 SEQ ID No: 525 rs705998 0.650.000030 Dominant 2.1 1.5-2.9 SEQ ID No: 225 SEQ ID No: 226 SEQ ID No:526 rs10517556 0.46 0.000067 Dominant 1.6 1.3-2   SEQ ID No: 227 SEQ IDNo: 228 SEQ ID No: 527 rs7081455 0.76 0.000010 Allele 1.5 1.2-1.8 SEQ IDNo: 29 SEQ ID No: 230 SEQ ID No: 528 rs547984 0.46 0.000056 Allele 1.31.2-1.5 SEQ ID No: 231 SEQ ID No: 232 SEQ ID No: 529 rs540782 0.460.000054 Dominant 1.6 1.3-2   SEQ ID No: 233 SEQ ID No: 234 SEQ ID No:530 SEQ ID No: 535 rs693421 0.46 0.000032 Dominant 1.6 1.3-2   SEQ IDNo: 235 SEQ ID No: 236 SEQ ID No: 531 rs2499601 0.46 0.000078 Dominant1.6 1.3-2   SEQ ID No: 237 SEQ ID No: 238 SEQ ID No: 532

Table 52 lists dbSNP ID number specifying known single nucleotidepolymorphisms obtained, the chromosome number at which a singlenucleotide polymorphism exists, the physical location of a singlenucleotide polymorphism, the exon, intron information (in a case where asingle nucleotide polymorphism exists on a gene, the gene name and theexon or intron in which SNP exists are shown, and in a case where asingle nucleotide polymorphism does not exist on a gene, neighboringgenes and a distance between the gene and the single nucleotidepolymorphism are shown), the information on the linkage disequilibriumstate (the numbers of LD1 to LD4 were assigned to single nucleotidepolymorphisms which exist in the same linkage disequilibrium region),each of bases constituting Allele 1 and Allele 2, the base of ahigh-risk allele, high-risk allele frequencies of the glaucoma patientgroup and the non-patient group, the p-value in a test method having thelowest p-value among three Mantel-Haenszel tests (allele frequency,dominant genetic model, and recessive genetic model), the kinds of thetests thereof, the odds ratio thereof, the 95% confidence intervalthereof, SEQ ID NO: of the sequence containing Allele 1 and SEQ ID NO:of the sequence containing Allele 2 in each of the polymorphic sites,and SEQ ID NO: showing a base sequence of a probe used in a secondaryanalysis (basically, both the alleles are detected by the same probe,and in a case where the alleles are discriminated using two kinds ofprobes, both the sequences are listed together.). Here, one of ordinaryskill in the art can obtain the information for sequences or alleles ofthe single nucleotide polymorphisms from dbSNP ID number listed above.

When the allele or genotype frequencies of the single nucleotidepolymorphisms listed in Table 52 were compared between the non-patientsand the glaucoma patients, a statistical difference was found accordingto Mantel-Haenszel chi-square test. By determining an allele of any oneof these single nucleotide polymorphisms in the same manner as that inExample 3, whether or not an allele that is identified in a higherfrequency in the glaucoma patient group than that of the non-patientgroup exists in the sample can be determined.

According to the above studies, 18 single nucleotide polymorphisms ofwhich alleles or genotypes were associated with glaucoma at a p-value of1.2×10⁻⁴ or less existing in clusters in relatively adjacent regions onthe genome were found in 11 regions.

An allele identified in a high frequency in the glaucoma patient groupfor single nucleotide polymorphisms listed in Table 52 (in other words,a high-risk allele) or a genotype (in other words,

-   -   a homozygote of a high-risk allele or a heterozygote when the        high-risk allele complies with a dominant genetic model, or a        homozygote of a high-risk allele when the high-risk allele        complies with a recessive genetic model) can be used as a marker        showing that an onset risk of glaucoma is high. On the other        hand, an allele that is opposite to the allele or a genotype        other than the genotype can be used as a marker showing that an        onset risk of glaucoma is low.

Similarly, a single nucleotide polymorphism of which allele or genotypeshows association with the onset of glaucoma at a p-value of 1×10⁻² orless, i.e. −log P of 2 or more is listed in Tables 53 to 62.

TABLE 53 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs429419 533,624,092 ADAMTS12 Intron17 (NM_030955.1) C G G 0.91 0.87 rs818725 533,624,060 ADAMTS12 Intron17 (NM_030955.1) C G G 0.91 0.87 rs10902569 1598,663,829 ADAMTS17 Intron3 (NM_139057.1) A G A 0.33 0.33 rs2387658 101,413,905 ADARB2 Intron1 (NM_018702.1) A C C 0.78 0.75 rs9881866 3106,304,709 ALCAM −264171bp (NM_001627.1) A G G 0.14 0.11 rs1342022 972,935,061 ANXA1 −61274bp (NM_000700.1) A G G 0.59 0.54 rs6097745 2052,101,533 BCAS1 Intron3 (NM_003657.1) A G A 0.30 0.27 rs2816632 14104,812,400 BRF1 Intron2 (NM_001519.2), A G G 0.21 0.16 BRF1 −27133bp(NM_145685.1), BRF1 −26587bp (NM_145696.1) rs16940484 18 19,936,298C18orf17 Intron6 (NM_153211.1) A G A 0.33 0.29 rs6115865 20 3,307,303C20orf194 −37687bp (XM_045421) A G A 0.39 0.33 rs1467913 3 50,500,021CACNA2D2 Intron2 (NM_006030.1) A C A 0.57 0.52 rs6786523 3 50,499,225CACNA2D2 Intron2 (NM_006030.1) A G A 0.57 0.52 rs12494849 3 50,499,562CACNA2D2 Intron2 (NM_006030.1) C G C 0.57 0.52 rs7571760 2 37,654,409CDC42EP3 +127985bp (NM_006449.3) A G A 0.40 0.35 rs10130333 1488,929,499 CHES1 Intron2 (NM_005197.1) A C A 0.66 0.64 Mantel- Mantel-95% Sequence Sequence Sequence 1 for Sequence 2 for Haenszel TestHaenszel Test Odds Confidence Containing Containing Secondary SecondarydBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis ProbeAnalysis Probe rs429419 0.002845 Allele 1.41 1.1-1.8 SEQ ID No: 239 SEQID No: 240 SEQ ID No: 536 SEQ ID No: 674 rs818725 0.003115 Allele 1.411.1-1.8 SEQ ID No: 241 SEQ ID No: 242 SEQ ID No: 537 SEQ ID No: 675rs10902569 0.004911 Recessive 1.60 1.2-2.2 SEQ ID No: 243 SEQ ID No: 244SEQ ID No: 538 rs2387658 0.001798 Recessive 1.39 1.1-1.7 SEQ ID No: 245SEQ ID No: 246 SEQ ID No: 539 rs9881866 0.006808 Allele 1.35 1.1-1.7 SEQID No: 247 SEQ ID No: 248 SEQ ID No: 540 rs1342022 0.000210 Recessive1.51 1.2-1.9 SEQ ID No: 249 SEQ ID No: 250 SEQ ID No: 541 rs60977450.006893 Dominant 1.32 1.1-1.6 SEQ ID No: 251 SEQ ID No: 252 SEQ ID No:542 rs2816632 0.002470 Allele 1.33 1.1-1.6 SEQ ID No: 253 SEQ ID No: 254SEQ ID No: 543 rs16940484 0.005060 Allele 1.25 1.1-1.5 SEQ ID No: 255SEQ ID No: 256 SEQ ID No: 544 rs6115865 0.000217 Dominant 1.47 1.2-1.8SEQ ID No: 257 SEQ ID No: 258 SEQ ID No: 545 rs1467913 0.001774 Dominant1.49 1.2-1.9 SEQ ID No: 259 SEQ ID No: 260 SEQ ID No: 546 rs67865230.001906 Dominant 1.49 1.2-1.9 SEQ ID No: 261 SEQ ID No: 262 SEQ ID No:547 rs12494849 0.005312 Allele 1.23 1.1-1.4 SEQ ID No: 263 SEQ ID No:264 SEQ ID No: 548 SEQ ID No: 676 rs7571760 0.000490 Recessive 1.681.3-2.2 SEQ ID No: 265 SEQ ID No: 266 SEQ ID No: 549 rs10130333 0.005714Dominant 1.53 1.1-2.1 SEQ ID No: 267 SEQ ID No: 268 SEQ ID No: 550

TABLE 54 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs493622 1189,882,297 CHORDC1 −286443bp (NM_012124.1) A C A 0.81 0.76 rs562160 1189,887,386 CHORDC1 −291532bp (NM_012124.1) A G G 0.81 0.76 rs2139539 131,786,872 COL16A1 +69bp (NM_001856.2) A G G 0.84 0.80 rs909002 131,808,728 COL16A1 Intron44 (NM_001856.2) A G G 0.81 0.77 rs7902091 1068,268,298 CTNNA3 Intron7 (NM_013266.1) A C A 0.50 0.45 rs2233476 350,363,387 CYB561D2 Exon1 (NM_007022.3) A C A 0.52 0.46 rs7676755 4187,490,196 CYP4V2 Intron2 (NM_207352.1) C G C 0.81 0.80 rs3862680 1848,184,338 DCC Intron (NM_005215.1) A C A 0.58 0.53 rs3862681 1848,184,688 DCC Intron (NM_005215.1) A G A 0.58 0.53 rs11737784 484,300,869 DKFZp686L1814 −11708bp A C C 0.79 0.76 (NM_194282.1)rs13137759 4 84,262,335 DKFZp686L1814 Intron2 A G A 0.79 0.76(NM_194282.1) rs12700287 7 21,385,860 DNAH11 Intron8 (NM_003777.1) C G C0.95 0.93 rs5765558 22 44,363,516 E46L −24767bp (NM_013236.1) A G A 0.580.53 rs4823324 22 44,558,660 E46L Intron10 (NM_013236.1) A G A 0.50 0.45rs1892116 1 243,406,363 ELYS Intron2 (NM_175865.1), A G A 0.75 0.70 ELYSIntron2 (NM_015446.1) Mantel- Mantel- 95% Sequence Sequence Sequence 1for Sequence 2 for Haenszel Test Haenszel Test Odds ConfidenceContaining Containing Secondary Secondary dBSNP ID p-value Model RatioInterval Allele 1 Allele 2 Analysis Probe Analysis Probe rs4936220.000467 Allele 1.36 1.1-1.6 SEQ ID No: 269 SEQ ID No: 270 SEQ ID No:551 rs562160 0.000696 Allele 1.35 1.1-1.6 SEQ ID No: 271 SEQ ID No: 272SEQ ID No: 552 rs2139539 0.008566 Dominant 2.36 1.2-4.5 SEQ ID No: 273SEQ ID No: 274 SEQ ID No: 553 rs909002 0.002649 Dominant 2.26 1.3-3.9SEQ ID No: 275 SEQ ID No: 276 SEQ ID No: 554 rs7902091 0.001835Recessive 1.47 1.2-1.9 SEQ ID No: 277 SEQ ID No: 278 SEQ ID No: 555rs2233476 0.000169 Dominant 1.55 1.2-1.9 SEQ ID No: 279 SEQ ID No: 280SEQ ID No: 556 rs7676755 0.006756 Dominant 1.96 1.2-3.2 SEQ ID No: 281SEQ ID No: 282 SEQ ID No: 557 SEQ ID No: 667 rs3862680 0.002299 Allele1.25 1.1-1.4 SEQ ID No: 283 SEQ ID No: 284 SEQ ID No: 558 rs38626810.002675 Allele 1.25 1.1-1.4 SEQ ID No: 285 SEQ ID No: 286 SEQ ID No:559 rs11737784 0.007584 Recessive 1.32 1.1-1.6 SEQ ID No: 287 SEQ ID No:288 SEQ ID No: 560 rs13137759 0.008987 Recessive 1.32 1.1-1.6 SEQ ID No:289 SEQ ID No: 290 SEQ ID No: 561 rs12700287 0.005463 Allele 1.541.1-2.1 SEQ ID No: 291 SEQ ID No: 292 SEQ ID No: 562 SEQ ID No: 678rs5765558 0.003829 Allele 1.24 1.1-1.4 SEQ ID No: 293 SEQ ID No: 294 SEQID No: 563 rs4823324 0.003204 Allele 1.24 1.1-1.4 SEQ ID No: 295 SEQ IDNo: 296 SEQ ID No: 564 rs1892116 0.002178 Allele 1.28 1.1-1.5 SEQ ID No:297 SEQ ID No: 298 SEQ ID No: 565

TABLE 55 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs9398995 6132,181.896 ENPP1 Intron1 (NM_006208.1) A G A 0.56 0.52 rs1441354 1569,517,251 FLJ13710 −290691bp (NM_024817.1) A T T 0.27 0.27 rs1012728 321,519,300 FLJ22419 Intron4 (NM_024697.1) A C C 0.48 0.43 rs3922704 3112,983,875 FLJ31579 Intron3 (NM_153268.1) C G G 0.88 0.83 rs1382851 1225,689,829 FLJ36004 −92384bp (NM_152590.1) A C C 0.57 0.53 rs$$144951 1551,643,802 FLJ38736 Intron17 (NM_182758.1) A G A 0.14 0.11 rs11750584 541,129,616 FLJ40243 −22454bp (NM_173489.2) C G C 0.20 0.16 rs9300981 13104,440,279 G30 +469126bp (XM_498445) A C C 0.64 0.59 rs9640055 77,802,756 GLCCI1 Intron1 (XM_166529) A G A 0.82 0.79 rs9852677 350,266,621 GNAI2 Intron4 (NM_002070.1) A G A 0.54 0.47 rs2236944 350,267,197 GNAI2 Intron4 (NM_002070.1) A C A 0.52 0.46 rs610160 11105,202,105 GRIA4 Intron3 (NM_000829.1) A G G 0.20 0.15 rs9498701 6102,336,911 GRIK2 Intron6 (NM_021956.2), A G A 0.59 0.54 GRIK2 Intron6(NM_175768.1) rs4840196 6 102,359,520 GRIK2 Intron8 (NM_021956.2), A T A0.59 0.54 GRIK2 Intron8 (NM_175768.1) rs4840195 6 102,359,490 GRIK2Intron8 (NM_021956.2), A G G 0.58 0.54 GRIK2 Intron8 (NM_175768.1)Mantel- Mantel- 95% Sequence Sequence Sequence 1 for Sequence 2 forHaenszel Test Haenszel Test Odds Confidence Containing ContainingSecondary Secondary dBSNP ID p-value Model Ratio Interval Allele 1Allele 2 Analysis Probe Analysis Probe rs9398995 0.008585 Recessive 1.351.1-1.7 SEQ ID No: 299 SEQ ID No: 300 SEQ ID No: 566 rs1441354 0.003800Recessive 1.92 1.2-3   SEQ ID No: 301 SEQ ID No: 302 SEQ ID No: 567 SEQID No: 679 rs1012728 0.001063 Dominant 1.44 1.2-1.8 SEQ ID No: 303 SEQID No: 304 SEQ ID No: 568 rs3922704 0.000294 Allele 1.46 1.2-1.8 SEQ IDNo: 305 SEQ ID No: 306 SEQ ID No: 569 SEQ ID No: 680 rs1382851 0.003765Dominant 1.45 1.1-1.9 SEQ ID No: 307 SEQ ID No: 308 SEQ ID No: 570rs$$144951 0.005496 Dominant 1.42 1.1-1.8 SEQ ID No: 309 SEQ ID No: 310SEQ ID No: 571 rs11750584 0.005023 Allele 1.31 1.1-1.6 SEQ ID No: 311SEQ ID No: 312 SEQ ID No: 572 SEQ ID No: 681 rs9300981 0.005027 Dominant1.50 1.1-2   SEQ ID No: 313 SEQ ID No: 314 SEQ ID No: 573 rs96400550.003780 Allele 1.30 1.1-1.6 SEQ ID No: 315 SEQ ID No: 316 SEQ ID No:574 rs9852677 0.000278 Allele 1.30 1.1-1.5 SEQ ID No: 317 SEQ ID No: 318SEQ ID No: 575 rs2236944 0.000383 Dominant 1.51 1.2-1.9 SEQ ID No: 319SEQ ID No: 320 SEQ ID No: 576 rs610160 0.002530 Allele 1.34 1.1-1.6 SEQID No: 321 SEQ ID No: 322 SEQ ID No: 577 rs9498701 0.000935 Recessive1.45 1.2-1.8 SEQ ID No: 323 SEQ ID No: 324 SEQ ID No: 578 rs48401960.001162 Recessive 1.44 1.2-1.8 SEQ ID No: 325 SEQ ID No: 326 SEQ ID No:579 SEQ ID No: 682 rs4840195 0.001597 Recessive 1.43 1.1-1.8 SEQ ID No:327 SEQ ID No: 328 SEQ ID No: 580

TABLE 56 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs9322609 6102,357,540 GRIK2 Intron8 (NM_021956.2), A G G 0.58 0.54 GRIK2 Intron8(NM_175768.1) rs2764236 6 102,389,150 GRIK2 Intron9 (NM_021956.2), A G A0.59 0.54 GRIK2 Intron9 (NM_175768.1) rs779701 3 7,493,772 GRM7 Intron7(NM_181875.1), A G G 0.33 0.28 GRM7 Intron7 (NM_000844.2), GRM7 Intron7(NM_181874.1) rs4430902 2 189,010,443 GULP1 Intron1 (NM_016315.1) A G A0.84 0.82 rs10271531 7 80,758,592 HGF +217504bp (NM_000601.3) A G A 0.410.36 rs4430896 2 23,246,431 KBTBD9 −239670bp (XM_496546) A G A 0.74 0.69rs17279573 4 154,937,893 KIAA0922 +22425bp (NM_015196.2) A G A 0.72 0.67rs1206153 6 97,652,757 KIAA1900 Intron6 (NM_052904.1) A G A 0.53 0.50rs4763559 12 10,622,909 KLRA1 +10130bp (NM_006611.1) C G G 0.75 0.70rs2125094 12 10,622,012 KLRA1 +11027bp (NM_006611.1) A G G 0.74 0.69rs11056970 12 16,558,431 LMO3 +34143bp (NM_018640.3), A C C 0.85 0.82LMO3 +34143bp (NM_001001395.1) rs8086430 18 20,600,317 LOC147468+250079bp (XM_091809) A G G 0.27 0.23 rs7910849 10 31,144,546 LOC220929+29028bp (NM_182755.1) A G A 0.73 0.68 rs1462840 3 118,345,185 LOC285194+426618bp (XM_379207) A G G 0.62 0.56 rs7612549 3 34,789,105 LOC285307+209732bp (XM_211837) A C C 0.42 0.39 Mantel- Mantel- 95% SequenceSequence Sequence 1 for Sequence 2 for Haenszel Test Haenszel Test OddsConfidence Containing Containing Secondary Secondary dBSNP ID p-valueModel Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probers9322609 0.001827 Recessive 1.42 1.1-1.8 SEQ ID No: 329 SEQ ID No: 330SEQ ID No: 581 rs2764236 0.001904 Recessive 1.42 1.1-1.8 SEQ ID No: 331SEQ ID No: 332 SEQ ID No: 582 rs779701 0.002130 Allele 1.28 1.1-1.5 SEQID No: 333 SEQ ID No: 334 SEQ ID No: 583 rs4430902 0.009243 Recessive1.33 1.1-1.7 SEQ ID No: 335 SEQ ID No: 336 SEQ ID No: 584 rs102715310.004906 Allele 1.23 1.1-1.4 SEQ ID No: 337 SEQ ID No: 338 SEQ ID No:585 rs4430896 0.008598 Allele 1.24 1.1-1.4 SEQ ID No: 339 SEQ ID No: 340SEQ ID No: 586 rs17279573 0.000685 Allele 1.31 1.1-1.5 SEQ ID No: 341SEQ ID No: 342 SEQ ID No: 587 rs1206153 0.001009 Recessive 1.47 1.2-1.9SEQ ID No: 343 SEQ ID No: 344 SEQ ID No: 588 rs4763559 0.000624 Allele1.32 1.1-1.5 SEQ ID No: 345 SEQ ID No: 346 SEQ ID No: 589 SEQ ID No: 683rs2125094 0.001004 Allele 1.30 1.1-1.5 SEQ ID No: 347 SEQ ID No: 348 SEQID No: 590 rs11056970 0.002381 Dominant 2.07 1.3-3.3 SEQ ID No: 349 SEQID No: 350 SEQ ID No: 591 rs8086430 0.006316 Allele 1.26 1.1-1.5 SEQ IDNo: 351 SEQ ID No: 352 SEQ ID No: 592 rs7910849 0.000272 Recessive 1.461.2-1.8 SEQ ID No: 353 SEQ ID No: 354 SEQ ID No: 593 rs1462840 0.000975Dominant 1.57 1.2-2.1 SEQ ID No: 355 SEQ ID No: 356 SEQ ID No: 594rs7612549 0.005641 Recessive 1.49 1.1-2   SEQ ID No: 357 SEQ ID No: 358SEQ ID No: 595

TABLE 57 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs6550308 334,911,573 LOC285307 +332200bp (XM_211837) A G G 0.46 0.40 rs10517578 4155,005,757 LOC285533 Intron4 (NM_173662.1) A G G 0.74 0.69 rs6468360 829,863,536 LOC286135 −35034bp (XM_379573) C G C 0.55 0.52 rs2040073 138,498,317 LOC339442 −148785bp (XM_378855) A G A 0.35 0.30 rs6431929 28,255,994 LOC339789 +41877bp (NM_207358.1) A G G 0.69 0.66 rs10488110 79,827,710 LOC340268 Intron1 (XM_294634) A G G 0.11 0.07 rs411102 999,196,524 LOC347265 +48076bp (XM_294590) A G A 0.14 0.10 rs782394 10130,349,442 LOC387721 −251645bp (XM_370585) A T A 0.53 0.49 rs10430126 147,934,070 LOC388630 +22702bp (XM_371250) A C C 0.63 0.58 rs4668312 2171,432,334 LOC389059 −20365bp (XM_374017) A G A 0.73 0.68 rs6433243 2171,431,002 LOC389059 −21697bp (XM_374017) A G G 0.73 0.68 rs10184230 2171,427,641 LOC389059 −25058bp (XM_374017) A G A 0.73 0.68 rs6746374 2171,445,013 LOC389059 −7686bp (XM_374017) A G A 0.73 0.68 rs10492680 1339,702,836 LOC400123 −23647bp (XM_378411) A G A 0.93 0.89 rs10228514 735,237,035 LOC40132 +47709bp (XM_379484) A C A 0.82 0.79 Mantel- Mantel-95% Sequence Sequence Sequence 1 for Sequence 2 for Haenszel TestHaenszel Test Odds Confidence Containing Containing Secondary SecondarydBSNP ID p-value Model Ratio Interval Allele 1 Allele 2 Analysis ProbeAnalysis Probe rs6550308 0.000835 Dominant 1.44 1.2-1.8 SEQ ID No: 359SEQ ID No: 360 SEQ ID No: 596 rs10517578 0.002228 Allele 1.28 1.1-1.5SEQ ID No: 361 SEQ ID No: 362 SEQ ID No: 597 rs6468360 0.003998Recessive 1.39 1.1-1.7 SEQ ID No: 363 SEQ ID No: 364 SEQ ID No: 598 SEQID No: 684 rs2040073 0.001364 Dominant 1.39 1.1-1.7 SEQ ID No: 365 SEQID No: 366 SEQ ID No: 599 rs6431929 0.004709 Dominant 1.59 1.2-2.2 SEQID No: 367 SEQ ID No: 368 SEQ ID No: 600 rs10488110 0.000465 Allele 1.591.2-2.1 SEQ ID No: 369 SEQ ID No: 370 SEQ ID No: 601 rs411102 0.000158Dominant 1.60 1.3-2.1 SEQ ID No: 371 SEQ ID No: 372 SEQ ID No: 602rs782394 0.001769 Recessive 1.46 1.2-1.8 SEQ ID No: 373 SEQ ID No: 374SEQ ID No: 603 SEQ ID No: 685 rs10430126 0.001484 Recessive 1.41 1.1-1.7SEQ ID No: 375 SEQ ID No: 376 SEQ ID No: 604 rs4668312 0.001698 Allele1.28 1.1-1.5 SEQ ID No: 377 SEQ ID No: 378 SEQ ID No: 605 rs64332430.001306 Allele 1.29 1.1-1.5 SEQ ID No: 379 SEQ ID No: 380 SEQ ID No:606 rs10184230 0.001306 Allele 1.29 1.1-1.5 SEQ ID No: 381 SEQ ID No:382 SEQ ID No: 607 rs6746374 0.001303 Allele 1.29 1.1-1.5 SEQ ID No: 383SEQ ID No: 384 SEQ ID No: 608 rs10492680 0.000655 Allele 1.55 1.2-2  SEQ ID No: 385 SEQ ID No: 386 SEQ ID No: 609 rs10228514 0.009024Recessive 1.33 1.1-1.6 SEQ ID No: 387 SEQ ID No: 388 SEQ ID No: 610

TABLE 58 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs17157033 1044,613,470 LOC439960 −30545bp (XM_498478) A C A 0.96 0.93 rs4307718 1123,320,437 LOC440033 +175532bp (XM_498512) A C C 0.95 0.93 rs6550783 323,719,090 LOC440947 −8191bp (XM_496633) A G A 0.68 0.63 rs16891164 414,590,288 LOC441009 +88767bp (XM_498965) A T T 0.95 0.93 rs339858 1820,466,188 LOC441816 −124776bp (XM_497584) A G A 0.15 0.11 rs17187933 1820,556,033 LOC441816 −214621bp (XM_497584) A G G 0.25 0.20 rs11876045 1820,564,102 LOC441816 −222690bp (XM_497584) C G C 0.26 0.22 rs17260163 1820,592,187 LOC441816 −250775bp (XM_497584) A G G 0.27 0.23 rs2004243 8143,815,988 LOC51337 +641bp (NM_016647.1) A G A 0.43 0.37 rs1990702 2169,802,022 LRP2 +8346bp (NM_004525.1) A G A 0.69 0.64 rs16883860 636,110,440 MAPK14 Intron1 (NM_139013.1), A G A 0.92 0.89 MAPK14 Intron1(NM_001315.1), MAPK14 Intron1 (NM_139012.1), MAPK14 Intron1(NM_139014.1) rs7761118 6 36,176,281 MAPK14 Intron9 (NM_139013.1), A G G0.92 0.89 MAPK14 Intron9 (NM_001315.1), MAPK14 Intron9 (NM_139012.1),MAPK14 Intron9 (NM_139014.1) rs2359112 1 34,548,776 MGC1582 +194951bp(NM_032884.2) A G A 0.33 0.31 rs16904092 8 130,571,112 MGC27434 Intron1(NM_145050.2) A G A 0.90 0.88 rs10764881 10 131,153,821 MGMT −70674bp(NM_002412.1) A G G 0.69 0.64 Mantel- Mantel- 95% Sequence SequenceSequence 1 for Sequence 2 for Haenszel Test Haenszel Test OddsConfidence Containing Containing Secondary Secondary dBSNP ID p-valueModel Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probers17157033 0.004744 Recessive 1.61 1.2-2.2 SEQ ID No: 389 SEQ ID No: 390SEQ ID No: 611 rs4307718 0.009971 Allele 1.51 1.1-2.1 SEQ ID No: 391 SEQID No: 392 SEQ ID No: 612 rs6550783 0.003108 Allele 1.25 1.1-1.5 SEQ IDNo: 393 SEQ ID No: 394 SEQ ID No: 613 rs16891164 0.003660 Allele 1.561.2-2.1 SEQ ID No: 395 SEQ ID No: 396 SEQ ID No: 614 SEQ ID No: 686rs339858 0.007997 Allele 1.34 1.1-1.7 SEQ ID No: 397 SEQ ID No: 398 SEQID No: 615 rs17187933 0.002141 Dominant 1.39 1.1-1.7 SEQ ID No: 399 SEQID No: 400 SEQ ID No: 616 rs11876045 0.003407 Dominant 1.36 1.1-1.7 SEQID No: 401 SEQ ID No: 402 SEQ ID No: 617 SEQ ID No: 687 rs172601630.006099 Allele 1.26 1.1-15  SEQ ID No: 403 SEQ ID No: 404 SEQ ID No:618 rs2004243 0.001099 Allele 1.27 1.1-1.5 SEQ ID No: 405 SEO ID No: 406SEO ID No: 619 rs1990702 0.004527 Allele 1.24 1.1-1.4 SEQ ID No: 407 SEQID No: 408 SEQ ID No: 620 rs16883860 0.002150 Allele 1.46 1.1-1.9 SEQ IDNo: 409 SEQ ID No: 410 SEQ ID No: 621 rs7761118 0.004398 Allele 1.421.1-1.8 SEQ ID No: 411 SEQ ID No: 412 SEQ ID No: 622 rs2359112 0.004022Recessive 1.74 1.2-2.5 SEQ ID No: 413 SEO ID No: 414 SEQ ID No: 623rs16904092 0.007732 Recessive 1.41 1.1-1.8 SEQ ID No: 415 SEQ ID No: 416SEQ ID No: 624 rs10764881 0.001557 Dominant 1.78 1.2-2.5 SEQ ID No: 417SEQ ID No: 418 SEQ ID No: 625

TABLE 59 High-Risk Allele High-Risk Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs11016249 10130,138,328 MKI67 −323870bp (NM_002417.2) A G G 0.68 0.64 rs2857648 2228,391,122 NF2 Intron10 (NM_181825.1), C G G 0.71 0.67 NF2 Intron8(NM_181831.1), NF2 Intron10 (NM_000268.2), NF2 Intron10 (NM_016418.4),NF2 Intron11 (NM_181826.1), NF2 Intron10 (NM_181827.1), NF2 Intron9(NM_181828.1), NF2 Intron9 (NM_181829.1), NF2 Intron8 (NM_181830.1), NF2Intron10 (NM_181832.1), NF2 Intron4 (NM_181833.1), NF2 Intron5(NM_181834.1), NF2 Intron8 (NM_181835.1) rs17808998 17 8,919,071 NTN1Intron2 (NM_004822.1) A G G 0.62 0.58 rs2072133 12 111,871,980 OAS3Exon16 (NM_006187.2) A G A 0.66 0.61 rs4666488 2 19,608,777 ODD−128777bp (NM_145260.1) A G A 0.38 0.33 rs10798882 1 31,777,640 PEFIntron1 (NM_012392.1) C G G 0.85 0.81 rs17754672 2 64,312,259 PEL11−61125bp (NM_020651.2) A G A 0.22 0.18 rs10116231 9 78,151,153 PSAT1Intron5 (NM_021154.3), A G G 0.76 0.71 PSAT1 Intron5 (NM_058179.2)rs2236913 1 223,380,860 PSEN2 Intron5 (NM_000447.1), A G G 0.37 0.34PSEN2 Intron5 (NM_012486.1) rs7574012 2 37,638,881 QPCT +126765bp(NM_012413.2) A G G 0.41 0.36 Mantel- Mantel- 95% Sequence SequenceSequence 1 for Sequence 2 for Haenszel Test Haenszel Test OddsConfidence Containing Containing Secondary Secondary dBSNP ID p-valueModel Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probers11016249 0.008687 Allele 1.22 1.1-1.4 SEQ ID No: 419 SEQ ID No: 420SEQ ID No: 626 rs2857648 0.006985 Recessive 1.32 1.1-1.6 SEQ ID No: 421SEQ ID No: 422 SEQ ID No: 627 SEQ ID No: 688 rs17808998 0.008779Recessive 1.33 1.1-1.6 SEQ ID No: 423 SEQ ID No: 424 SEQ ID No: 628rs2072133 0.003090 Allele 1.25 1.1-1.4 SEQ ID No: 425 SEQ ID No: 426 SEQID No: 629 rs4666488 0.000309 Dominant 1.46 1.2-1.8 SEQ ID No: 427 SEQID No: 428 SEQ ID No: 630 rs10798882 0.001679 Allele 1.36 1.1-1.6 SEQ IDNo: 429 SEQ ID No: 430 SEQ ID No: 631 SEQ ID No: 689 rs17754672 0.006631Recessive 2.36 1.3-4.4 SEQ ID No: 431 SEQ ID No: 432 SEQ ID No: 632rs10116231 0.003816 Allele 1.27 1.1-1.5 SEQ ID No: 433 SEQ ID No: 434SEQ ID No: 633 rs2236913 0.009042 Dominant 1.32 1.1-1.6 SEQ ID No: 435SEQ ID No: 436 SEQ ID No: 634 rs7574012 0.001545 Recesssive 1.59 1.2-2.1SEQ ID No: 437 SEQ ID No: 438 SEQ ID No: 635

TABLE 60 High-Risk High-Risk Allele Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs6724538 237,639,669 QPCT +127553bp (NM_012413.2) A C A 0.41 0.35 rs7584987 237,641,805 QPCT +129689bp (NM_012413.2) A G G 0.44 0.39 rs1877823 1760,657,405 RGS9 +3136bp (NM_003835.1) A G A 0.77 0.74 rs9896245 1760,604,218 RGS9 −11066bp (NM_003835.1) A G A 0.74 0.71 rs1877821 1760,605,875 RGS9 −9409bp (NM_003835.1) A G G 0.74 0.72 rs16865980 27,255,254 RNF144 +120346bp (NM_014746.2) A G A 0.25 0.21 rs9788983 17129,457 RPH3AL Intron6 (NM_006987.2) A G A 0.88 0.84 rs17115925 1481,341,217 SEL1L −271331bp (NM_005065.3) A T T 0.73 0.70 rs1571379 1481,359,690 SEL1L −289804bp (NM_005065.3) A G A 0.73 0.67 rs12632110 350,199,229 SEMA3F Intron18 (NM_004186.2) A G A 0.52 0.47 rs1951626 1170,623,758 SERPINC1 −5704bp (NM_000488.1) A G A 0.36 0.31 rs2044757 3155,352,950 SGEF Intron5 (NM_015595.2) A G G 0.64 0.61 rs33954719 3155,359,077 SGEF Intron6 (NM_015595.2) A G A 0.64 0.61 rs3761980 636,101,884 SLC26A8 −1529bp (NM_052961.2), A G A 0.92 0.89 SLC26A8−1636bp (NM_138718.1) rs1606405 13 82,684,518 SLITRK1 +664827bp(NM_052910.1) A G A 0.54 0.50 Mantel- Mantel- 95% Sequence SequenceSequence 1 for Sequence 2 for Haenszel Test Haenszel Test OddsConfidence Containing Containing Secondary Secondary dBSNP ID p-valueModel Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probers6724538 0.000321 Recessive 1.69 1.3-2.2 SEQ ID No: 439 SEQ ID No: 440SEQ ID No: 636 rs7584987 0.000572 Recessive 1.60 1.2-2.1 SEQ ID No: 441SEQ ID No: 442 SEQ ID No: 637 rs1877823 0.001810 Dominant 1.98 1.3-3  SEQ ID No: 443 SEQ ID NO: 444 SEQ ID No: 638 rs9896245 0.000141 Dominant2.19 1.5-3.3 SEQ ID No: 445 SEQ ID No: 446 SEQ ID No: 639 rs18778210.000419 Dominant 2.10 1.4-3.2 SEQ ID No: 447 SEQ ID No: 448 SEQ ID No:640 rs16865980 0.000687 Dominant 1.43 1.2-1.8 SEQ ID No: 449 SEQ ID No:450 SEQ ID No: 641 rs9788983 0.000891 Allele 1.42 1.2-1.7 SEQ ID No: 451SEQ ID No: 452 SEQ ID No: 642 rs17115925 0.009837 Allele 1.23 1.1-1.4SEQ ID No: 453 SEQ ID No: 454 SEQ ID No: 643 SEQ ID No: 690 rs15713790.000529 Allele 1.32 1.1-1.5 SEQ ID No: 455 SEQ ID No: 456 SEQ ID No:644 rs12632110 0.000586 Dominant 1.50 1.2-1.9 SEQ ID No: 457 SEQ ID No:458 SEQ ID No: 645 rs1951626 0.009171 Allele 1.22 1.1-1.4 SEQ ID No: 459SEQ ID No: 460 SEQ ID No: 646 rs2044757 0.001153 Dominant 1.61 1.2-2.1SEQ ID No: 461 SEQ ID No: 462 SEQ ID No: 647 rs33954719 0.001078Dominant 1.61 1.2-2.2 SEQ ID No: 463 SEQ ID No: 464 SEQ ID No: 648rs3761980 0.002750 Allele 1.44 1.1-1.8 SEQ ID No: 465 SEQ ID No: 466 SEQID No: 649 rs1606405 0.002823 Recessive 1.42 1.1-1.8 SEQ ID No: 467 SEQID No: 468 SEQ ID No: 650

TABLE 61 High-Risk Allele High-Risk Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs2356232 2171,412,281 SP5 +1227bp (XM_371581) A G A 0.73 0.68 rs7608898 2171,423,724 SP5 +23719bp (XM_371581) A G A 0.73 0.68 rs10930437 2171,406,848 SP5 +6843bp (XM_371581) A G A 0.73 0.68 rs4667649 2171,408,395 SP5 +8390bp (XM_371581) A G A 0.73 0.68 rs2049723 1113,922,920 SPON1 −17894bp (NM_006108.1) A G A 0.74 0.69 rs2268794 231,691,055 SRD5A2 Intron1 (NM_000348.2) A T A 0.19 0.15 rs1106845 1435,931,107 STELLAR +19768bp (XM_375075) A T T 0.10 0.07 rs2966712 7142,683,960 TAS2R41 −7843bp (NM_176883.1) A G A 0.11 0.07 rs1658456 1059,974,332 TFAM +148429bp (NM_003201.1), A G G 0.58 0.53 TFAM +158914bp(NM_012251.1) rs1649060 10 59,980,486 TFAM +154583bp (NM_003201.1), C GC 0.58 0.53 TFAM +165068bp (NM_012251.1) rs1649048 10 59,994,288 TFAM+168385bp (NM_003201.1), A G G 0.58 0.53 TFAM +178870bp (NM_012251.1)rs1658438 10 59,996,589 TFAM +170686bp (NM_003201.1), A G G 0.58 0.52TFAM +181171bp (NM_012251.1) rs1649039 10 60,000,047 TFAM +174144bp(NM_003201.1), A G G 0.57 0.52 TFAM +184629bp (NM_012251.1) rs1076355810 60,011,940 TFAM +186037bp (NM_003201.1), A C C 0.57 0.52 TFAM+196522bp (NM_012251.1) rs11727442 4 154,943,527 TLR2 −23144bp(NM_003264.2) A G G 0.69 0.64 Mantel- Mantel- 95% Sequence SequenceSequence 1 for Sequence 2 for Haenszel Test Haenszel Test OddsConfidence Containing Containing Secondary Secondary dBSNP ID p-valueModel Ratio Interval Allele 1 Allele 2 Analysis Probe Analysis Probers2356232 0.001522 Allele 1.29 1.1-1.5 SEQ ID No: 469 SEQ ID No: 470 SEQID No: 651 rs7608898 0.001306 Allele 1.29 1.1-1.5 SEQ ID No: 471 SEQ IDNo: 472 SEQ ID No: 652 rs10930437 0.001587 Allele 1.29 1.1-1.5 SEQ IDNo: 473 SEQ ID No: 474 SEQ ID No: 653 rs4667649 0.001662 Allele 1.281.1-1.5 SEQ ID No: 475 SEQ ID No: 476 SEQ ID No: 654 rs2049723 0.002649Allele 1.27 1.1-1.5 SEQ ID No: 477 SEQ ID No: 478 SEQ ID No: 655rs2268794 0.006152 Allele 1.31 1.1-1.6 SEQ ID No: 479 SEQ ID No: 480 SEQID No: 656 SEQ ID No: 691 rs1106845 0.006141 Allele 1.45 1.1-1.9 SEQ IDNo: 481 SEQ ID No: 482 SEQ ID No: 657 SEQ ID No: 692 rs2966712 0.000304Dominant 1.66 1.3-2.2 SEQ ID No: 483 SEQ ID No: 484 SEQ ID No: 658rs1658456 0.006414 Allele 1.22 1.1-1.4 SEQ ID No: 485 SEQ ID No.486 SEQID No: 659 rs1649060 0.006414 Allele 1.22 1.1-1.4 SEQ ID No: 487 SEQ IDNo: 488 SEQ ID No: 660 SEQ ID No: 693 rs1649048 0.006480 Allele 1.221.1-1.4 SEQ ID No: 489 SEQ ID No: 490 SEQ ID No: 661 rs1658438 0.006270Allele 1.22 1.1-1.4 SEQ ID No: 491 SEQ ID No: 492 SEQ ID No: 662rs1649039 0.007438 Allele 1.22 1.1-1.4 SEQ ID No: 493 SEQ ID No: 494 SEQID No: 663 rs10763558 0.008997 Allele 1.21 1.1-1.4 SEQ ID No: 495 SEQ IDNo: 496 SEQ ID No: 664 rs11727442 0.000624 Recessive 1.43 1.2-1.8 SEQ IDNo. 497 SEQ ID No: 498 SEQ ID No: 665

TABLE 62 High-Risk Allele High-Risk Allele Frequency in Frequency inPhysical High-Risk Glaucoma Non-Patient dBSNP ID Chromosome LocationExon, Intron Allele 1 Allele 2 Allele Patient Group Group rs3804100 4154,983,014 TLR2 Exon2 (NM_003264.2) A G A 0.73 0.68 rs1028534 1051,898,627 TMEM23 Intron3 (NM_147156.3) A C C 0.63 0.60 rs1210065 1051,882,795 TMEM23 Intron5 (NM_147156.3) A G A 0.40 0.35 rs17473451 815,368,500 TUSC3 −73601bp (NM_006765.2), C G C 0.76 0.72 TUSC3 −73601bp(NM_178234.1) rs6829490 4 47,908,795 TXK +894bp (NM_003328.1) A G G 0.540.49 rs500629 11 113,550,770 ZBTB16 Intron3 (NM_006006.3) A C C 0.280.23 rs2864107 19 56,760,839 ZNF175 −5504bp (NM_007147.2) A G A 0.210.17 rs3755827 3 62,335,411 ZNF12 −1350bp (NM_018008.2) A G A 0.79 0.74Mantel- Mantel- 95% Sequence Sequence Sequence 1 for Sequence 2 forHaenszel Test Haenszel Test Odds Confidence Containing ContainingSecondary Secondary dBSNP ID p-value Model Ratio Interval Allele 1Allele 2 Analysis Probe Analysis Probe rs3804100 0.003499 Allele 1.261.1-1.5 SEQ ID No: 499 SEQ ID No: 500 SEQ ID No: 666 rs1028534 0.005678Dominant 1.48 1.1-2   SEQ ID No: 501 SEQ ID No: 502 SEQ ID No: 667rs1210065 0.001850 Dominant 1.39 1.1-1.7 SEQ ID No: 503 SEQ ID No: 504SEQ ID No: 668 rs17473451 0.003504 Recessive 1.35 1.1-1.7 SEQ ID No: 505SEQ ID No: 506 SEQ ID No: 669 SEQ ID No: 694 rs6829490 0.009776 Dominant1.37 1.1-1.7 SEQ ID No: 507 SEQ ID No: 508 SEQ ID No: 670 rs5006290.001621 Dominant 1.39 1.1-1.7 SEQ ID No: 509 SEQ ID No: 510 SEQ ID No:671 rs2864107 0.000428 Dominant 1.47 1.2-1.8 SEQ ID No: 511 SEQ ID No:512 SEQ ID No: 672 rs3755827 0.004467 Allele 1.28 1.1-1.5 SEQ ID No: 513SEQ ID No: 514 SEQ ID No: 673

The single nucleotide polymorphisms listed in Tables 53 to 62 can bealso used as a marker for predicting an onset risk of glaucoma in thesame manner.

Next, regions and/or genes of the surrounding of single nucleotidepolymorphism listed in Table 52 were determined by making reference tothe database provided by the HapMap project. In detail, regions in whichthe single nucleotide polymorphism considered to be in a linkagedisequilibrium with the single nucleotide polymorphisms listed in Table52 exists were determined, on the basis of the linkage disequilibriumdata in combination of the Japanese and the Chinese in the HapMapproject.

Also, in a case where the single nucleotide polymorphism listed in

Table 52 exists in the linkage disequilibrium region containing genes,the physical location of the region and the gene name were determined.On the other hand, in a case where the single nucleotide polymorphismlisted in Table 52 exists in the linkage disequilibrium region withoutcontaining the genes, only the physical location of the region wasdetermined. In addition, in a case where the single nucleotidepolymorphism listed in Table 52 exists on one gene beyond the linkagedisequilibrium region, the gene name and the physical location of thegene were determined.

A single nucleotide polymorphism of which p-value is the lowest for eachregion is considered to be a single nucleotide polymorphism representingthe region, and Tables 63 to 70 list a single nucleotide polymorphismrepresenting the region, the chromosome number at which the regionexists, the physical location of the region (start point and end point)and the gene name contained in the region.

TABLE 63 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs10798882 1 31,707,05531,838,861 COL16A1 LCN7 HCRTR1 PEF1 rs2359112 1 34,477,408 34,552,678 —rs2040073 1 38,408,125 38,527,689 — rs10430126 1 47,930,338 48,198,192 —rs1951626 1 170,033,793 171,848,859 TNN MRPS14 CACYBP RABGAP1L RC3H1SERPINC1 ZBTB37 DARS2 CENPL KLHL20 ANKRD45 SLC9A11 PRDX6 rs2236913 1223,126,127 223,405,511 ITPKB PSEN2 rs693421 1 234,339,548 234,432,433ZP4 rs1892116 1 243,319,348 243,497,348 ZNF695 ELYS AHCTF1 rs16865980 27,200,812 7,280,358 — rs6431929 2 8,187,182 8,419,147 LOC339789rs4666488 2 19,472,875 19,608,452 OSR1 rs4430896 2 23,145,684 23,366,310—

TABLE 64 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs2268794 2 31,468,83933,038,731 XDH SRD5A2 MEMO1 DPY30 SPAST SLC30A6 NLRC4 YIPF4 BIRC6 TTC27rs6724538 2 37,588,322 37,740,529 — rs17754672 2 62,704,890 64,419,622EHBP1 OTX1 LOC51057 MDH1 UGP2 VPS54 PELI1 rs12611812 2 124,499,094125,389,091 CNTNAP5 rs7559118 2 133,263,104 134,159,763 NAP5 FLJ34870rs1990702 2 169,796,465 170,044,629 LRP2 rs6746374 2 171,322,396171,550,925 AK127400 GAD1 SP5 LOC440925 rs4430902 2 188,685,976189,579,329 GULP1 DIRC1 rs779701 3 6,877,927 7,758,217 GRM7 rs1012728 321,437,673 21,767,820 ZNF385D rs6550783 3 23,654,468 23,750,569 —

TABLE 65 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs6550308 3 34,785,78835,165,798 — rs2233476 3 49,686,439 51,799,207 APEH MST1 RNF123 AMIGO3GMPPB IHPK1 LOC389118 C3orf54 UBA7 TRAIP CAMKV MST1R MON1A RBM6 RBM5SEMA3F GNAT1 SLC38A3 GNAI2 SEMA3B IFRD2 NAT6 C3orf45 HYAL3 HYAL1 HYAL2TUSC2 RASSF1 ZMYND10 TUSC4 CYB561D2 TMEM115 CACNA2D2 C3orf18 HEMK1 CISHMAPKAPK3 DOCK3 ARMET RBM15B VPRBP RAD54L2 TEX264 GRM2

TABLE 66 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs3755827 3 62,280,43662,836,094 C3orf14 CADPS ZNF312 rs9881866 3 106,122,067 106,319,409 —rs3922704 3 112,876,213 113,177,795 PLCXD2 CR749654 AY358772 rs1462840 3118,332,596 118,498,089 — rs33954719 3 155,198,039 155,457,039 SGEFrs16891164 4 14,149,949 14,598,571 BC036758 rs6829490 4 47,436,94848,813,871 CORIN NFXL1 CNGA1 NPAL1 TXK TEC SLAIN2 ZAR1 FRYL OCIAD1OCIAD2 rs10517556 4 62,191,605 63,083,785 LPHN3 rs11737784 4 83,907,86984,368,310 SCD5 SEC31A THAP9 LIN54 COPS4 rs13110551 4 140,152,121140,188,487 — rs11727442 4 154,745,157 155,130,602 KIAA0922 TLR2 RNF175SFRP2 rs7676755 4 187,346,286 187,611,026 TLR3 DKFZP564J102 CYP4V2 KLKB1F11

TABLE 67 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs429419 5 33,563,046 33,927,881ADAMTS12 rs6451268 5 36,139,171 36,337,761 DKFZp434H2226 SKP2 FLJ30596FLJ25422 rs11750584 5 41,033,879 41,298,707 FLJ40243 C6 rs9358578 622,707,365 22,854,322 LOC389370 rs16883860 6 36,015,011 36,252,339SLC26A8 MAPK14 MAPK13 rs1206153 6 97,479,326 97,864,503 KIAA1900C6orf167 rs9498701 6 101,953,626 102,624,651 GRIK2 rs9398995 6132,000,135 132,286,336 ENPP3 ENPP1 rs9640055 7 7,772,656 8,075,425 ICA1GLCCI1 rs10488110 7 9,768,215 9,875,870 — rs12700287 7 21,338,07521,714,695 DNAH11 rs10228514 7 35,169,289 35,359,069 — rs10271531 780,612,379 80,941,240 — rs2966712 7 142,596,643 142,732,627 ZYX EPHA1TAS2R60 TAS2R41 rs17473451 8 15,324,913 15,422,271 — rs6468360 829,800,821 29,866,436 — rs16935718 8 69,986,592 70,338,390 ratara.bAug05 swakoy.aAug05 LOC389667 rs16904092 8 130,556,102 130,700,866 —

TABLE 68 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs2004243 8 143,716,339143,900,127 JRK PSCA LY6K C8orf55 SLURP1 LYNX1 LYPD2 LY6D rs1342022 972,743,457 72,939,880 ALDH1A1 rs10116231 9 78,136,500 78,174,561 PSAT1rs411102 9 99,100,781 99,364,219 — rs7850541 9 132,883,652 133,218,347GFI1B CR615294 GTF3C5 CEL CELP RALGDS GBGT1 OBP2B ABO rs2387658 101,218,073 1,769,718 ADARB2 rs7081455 10 20,662,930 20,719,326 —rs7910849 10 31,072,503 31,165,996 — rs17157033 10 44,456,300 44,698,295— rs1210065 10 51,696,167 52,116,588 TMEM23 AK056520 rs1658438 1059,803,487 60,258,851 BICC1 TFAM rs7902091 10 67,349,937 69,125,933CTNNA3 rs11016249 10 129,959,024 130,173,385 — rs782394 10 130,233,084130,350,260 — rs10764881 10 131,138,138 131,455,356 MGMT rs2049723 1113,850,243 14,246,222 SPON1 rs4307718 11 23,202,964 23,481,112 —

TABLE 69 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs493622 11 89,679,11290,004,712 — rs610160 11 104,896,113 105,358,029 GRIA4 rs500629 11113,435,641 113,626,604 ZBTB16 rs4763559 12 10,539,469 10,726,280 KLRA1FLJ10292 STYK1 rs11056970 12 16,468,226 16,587,335 — rs1382851 1225,669,680 25,892,423 — rs7961953 12 81,537,331 82,030,531 TMTC2rs2072133 12 111,807,459 111,912,247 OAS1 OAS2 OAS3 rs10492680 1339,608,046 39,760,155 — rs1606405 13 82,325,708 82,739,954 BC016673rs9300981 13 104,391,167 104,481,207 — rs1106845 14 35,808,12435,947,704 MBIP rs1571379 14 81,213,431 81,378,859 — rs10130333 1488,692,269 89,155,247 CHES1 rs2816632 14 104,746,671 104,838,374 BRF1BTBD6 rs4144951 15 51,558,394 51,892,014 WDR72 rs1441354 15 69,220,84269,862,776 THSD4 rs10902569 15 98,329,166 98,699,706 ADAMTS17 rs978898317 62,294 271,176 RPH3AL LOC400566 rs17808998 17 8,845,288 9,088,042NTN1 rs9896245 17 60,532,473 60,654,283 RGS9 rs1877823 17 60,564,01160,680,796 RGS9 rs16940484 18 19,826,735 20,231,788 C18orf17 OSBPL1ACABYR rs17187933 18 20,389,931 20,699,770 —

TABLE 70 Representative Single Nucleotide Polymorphism in the Region(Single Nucleotide Polymorphism Start End Genes in with Lowest p-value)Chromosome Location Location the Region rs3862680 18 48,050,18449,311,780 DCC rs2864107 19 56,686,425 56,784,802 SIGLEC12 ZNF175SIGLEC6 rs6115865 20 3,156,064 3,351,824 SLC4A11 C20orf194 rs6097745 2051,935,413 52,170,007 BCAS1 rs2857648 22 28,153,305 28,436,178 RFPL1NEFH THOC5 NIPSNAP1 NF2 rs4823324 22 44,219,256 44,580,747 FBLN1 ATXN10

The region listed in Tables 63 to 70 is a region or gene considered tobe linked with a single nucleotide polymorphism associated with theonset of glaucoma in the present invention listed in Tables 53 to 62,and a single nucleotide polymorphism which exists in these regions orgenes is considered to be linked with a single nucleotide polymorphismin the present invention. In other words, any single nucleotidepolymorphisms which exist in these regions are linked with the singlenucleotide polymorphism which exists in the region listed in Tables 53to 62, and any of these single nucleotide polymorphisms can be used inthe prediction of an onset risk of glaucoma in the same manner.

Example 11 Logistic Regression Analysis

In the present invention, by combining any two or more single nucleotidepolymorphisms determined to be involved in the onset of glaucoma, anextent to which the precision of the prediction of a risk of a diseaseimproves is examined with logistic regression analysis, as compared tothat where each of the single nucleotide polymorphisms is used alone. Inthe present analysis, any combinations of the single nucleotidepolymorphisms determined to be significantly associated with the onsetof glaucoma by statistically comparing allele or genotype frequenciescan be used. In one example, 17 single nucleotide polymorphisms thatshowed a significant difference under the Bonferroni correction weresubjected to the logistic regression analysis.

Out of 17 single nucleotide polymorphisms that had a significance underthe Bonferroni correction, single nucleotide polymorphisms for use inthe logistic regression analysis were further narrowed down according toa stepwise method. The value of 0.01 was adopted as criteria of variableincorporation and variable exclusion in the stepwise method. Upon theapplication of a stepwise method, a single nucleotide polymorphismbelonging to the same LD block (ones having the same description in thecolumn of linkage disequilibrium in Table 52) is represented by any oneof single nucleotide polymorphisms belonging to each of the LD blocks,and it is set so that any one of the single nucleotide polymorphisms isto be a subject to be incorporated. Each of the narrowed-down singlenucleotide polymorphisms is defined as an independent variable (Π)(homozygote of one allele=0, heterozygote=1, homozygote of oppositeallele=2), and each regression coefficient (λ) can be determinedaccording to the logistic regression analysis, and the following formula(18) was obtained formula (18)

Φ=1/{1+exp[−(λ0+λ1Π1+λ2Π2+λ3Π3+ . . . )]}Next, in each sample, a value for risk prediction (Φ) was calculated bysubstituting a variable for each single nucleotide polymorphisms intothis formula. When Φ is greater than 0.5, this sample donor wasdetermined to be with an onset risk. A concordance rate was calculatedby comparing the determination results with the matter of whether thesample donor having a single nucleotide polymorphism was actually aglaucoma patient. Further, the concordance rate was determined asmentioned above for each of the incorporated single nucleotidepolymorphisms alone, and all the combinations of any two or more singlenucleotide polymorphisms, and means and standard deviations of theconcordance rate were obtained for each of the number of singlenucleotide polymorphisms used in combination. Table 71 lists the numberof single nucleotide polymorphisms, alone or in a combination ofarbitrary number, the number of combinations when arbitrary number ofsingle nucleotide polymorphism is combined, and the relationship betweenthe mean and the standard deviation of the concordance rate. Here, allthe calculations were performed using SAS 9.1.3, Windows (registeredtrademark) Edition, SAS Institute Japan Corporation.

As listed in Table 71, according to a stepwise method, out of the 17single nucleotide polymorphisms, assuming that a pair of singlenucleotide polymorphisms belonging to the same LD block were eachcounted as one, all ten single nucleotide polymorphisms were selected(rs7081455, rs693421, rs9358578, rs7961953, rs16935718, rs11123034,rs13110551, rs7559118, rs10517556, and rs6451268). A value for riskprediction (Φ) of individual cases was calculated using a logisticregression formula, alone or in a combination of any two or more ofthese 10 single nucleotide polymorphisms. When a cut-off value for avalue for risk prediction is defined as 0.5, mean±standard deviation ofthe concordance rate was 54.7±1.4% in a case that each of the singlenucleotide polymorphisms was used alone. This concordance rate waselevated as an increase in the number of single nucleotide polymorphismsused in combination, and reached the maximum of 59.9% in a case that allthe ten were combined.

TABLE 71 The Number The Number of Concordance Rate Standard of SNPCombination (Mean Value) Deviation 1 10 54.7 1.4 2 45 55.7 1.1 3 12056.3 1.0 4 210 57.0 1.0 5 252 57.5 1.0 6 210 58.0 1.0 7 120 58.4 1.0 845 58.8 1.0 9 10 59.1 0.9 10 1 59.9 —

As described above, it was evident that in the determination of an onsetrisk of glaucoma by a single nucleotide polymorphism, an excellentconcordance rate can be obtained even in a case that each of the singlenucleotide polymorphisms are used alone, and the diagnostic precisioncan be further enhanced by combining these single nucleotidepolymorphisms.

As described above, an individual who has an allele or a genotype thatis identified in a high frequency in the glaucoma patients disclosed inthe present invention on the genome has a high onset risk of glaucoma infuture, and an individual who does not have an allele or a genotype thatis identified in a high frequency in the glaucoma patients has a lowonset risk of glaucoma in future.

INDUSTRIAL APPLICABILITY

According to the method of the present invention, the level of an onsetrisk of glaucoma of a sample donor can be determined by analyzing anallele or a genotype of a single nucleotide polymorphism in the presentinvention in a sample. A sample donor can take a preventive measure ofglaucoma, or can receive appropriate treatments, on the basis of thisrisk. In addition, it is useful because, a sample donor who has anallele or a genotype that is identified in a high frequency in theglaucoma patients of a single nucleotide polymorphism in the presentinvention on the genome can be given a precision examination in whetheror not the donor is with an early glaucoma which is difficult to bedetermined sufficiently by an intraocular pressure or an ocular fundusphotograph, and can be started with a treatment at an early stage in acase where the donor is diagnosed as glaucoma.

1. A method of determining the presence or the absence of a glaucomarisk, comprising: A. detecting in vitro an allele and/or a genotype of asingle nucleotide polymorphism which is located on a 31st base of a basesequence, in a sample from a subject, wherein the base sequence is atleast one base sequence selected from the group consisting of basesequences shown in SEQ ID NOs: 203 to 514 or a complementary sequencethereto, and B. comparing the allele and/or the genotype detected in Awith at least one of an allele and/or a genotype, comprising a high-riskallele, in the base sequences shown in SEQ ID NOs: 203 to 514, whereinthe presence of a glaucoma risk is determined in a case where the alleledetected in A is the high-risk allele, or wherein the presence of aglaucoma risk is determined in a case where the genotype detected in Ais a homozygote of the genotype comprising the high-risk allele or aheterozygote when the high-risk allele complies with a dominant geneticmodel, or wherein the presence of a glaucoma risk is determined in acase where the genotype detected in A is a homozygote of the genotypecomprising the high-risk allele when the high-risk allele complies witha recessive genetic model.
 2. The method according to claim 1, whereinthe glaucoma risk is an onset risk of glaucoma.
 3. The method accordingto claim 2, wherein the base sequence is selected from the groupconsisting of base sequences shown in SEQ ID NOs: 203 to
 238. 4. Themethod according to claim 3, wherein the comparison in B comprisesselecting and combining any two or more alleles and/or genotypes,comprising the high-risk allele, in the base sequences shown in SEQ IDNOs: 203 to 238, wherein the presence of a glaucoma risk is determinedin a case where the allele detected in A is any one of the allelesselected for the comparison in B, or wherein the presence of a glaucomarisk is determined in a case where the genotype detected in A is ahomozygote or a heterozygote of any one of the genotypes selected forthe comparison in B when the high-risk allele complies with a dominantgenetic model, or wherein the presence of a glaucoma risk is determinedin a case where the genotype detected in A is a homozygote of any one ofthe genotypes selected for the comparison in B when the high-risk allelecomplies with a recessive genetic model.
 5. The method according toclaim 4, wherein the comparison in B comprises selecting and combiningall the alleles and/or the genotypes, comprising the high-risk allele,in the base sequences shown in SEQ ID NOs: 203 to 238, wherein thepresence of a glaucoma risk is determined in a case where the alleledetected in A is any one of the alleles selected for the comparison inB, or wherein the presence of a glaucoma risk is determined in a casewhere the genotype detected in A is a homozygote or a heterozygote ofany one of the genotypes selected for the comparison in the B when thehigh-risk allele complies with a dominant genetic model, or wherein thepresence of a glaucoma risk is determined in a case where the genotypedetected in A is a homozygote of any one of the genotypes selected forthe comparison in B when the high-risk allele complies with a recessivegenetic model.
 6. The method according to claim 2, further comprisingpredicting the level of the onset risk.
 7. The method according to claim1, wherein the glaucoma is primary open-angle glaucoma (POAG) or normaltension glaucoma (NTG).
 8. A method of determining the presence or theabsence of a glaucoma risk, comprising: C1. detecting in vitro, in asample from a subject, an allele and/or a genotype of a singlenucleotide polymorphism which is located on a 31st base of a basesequence in a nucleic acid molecule, wherein the nucleic acid moleculecomprises at least one base sequence selected from the group consistingof base sequences shown in SEQ ID NOs: 203 to 514 or a complementarysequence thereto, or C2. detecting in vitro, in a sample from a subject,an allele and/or a genotype of a single nucleotide polymorphism, using anucleic acid molecule comprising a base sequence comprising at least onebase sequence selected from the group consisting of base sequences shownin SEQ ID NOs: 515 to 694 or a complementary sequence thereto, and D.comparing the allele and/or the genotype detected in C1 or C2 with atleast one nucleic acid molecule comprising an allele and/or a genotype,comprising a high-risk allele, in the base sequences shown in the SEQ IDNOs: 203 to 514, wherein the presence of a glaucoma risk is determinedin a case where the allele detected in C1 or C2 is the high-risk allele,or wherein the presence of a glaucoma risk is determined in a case wherethe genotype detected in C1 or C2 is a homozygote of the genotypecomprising the high-risk allele or a heterozygote when the high-riskallele complies with a dominant genetic model, or wherein the presenceof a glaucoma risk is determined in a case where the genotype detectedin C1 or C2 is a homozygote of the genotype comprising the high-riskallele when the high-risk allele complies with a recessive geneticmodel.
 9. The method according to claim 8, wherein the glaucoma risk isan onset risk of glaucoma.
 10. The method according to claim 9, whereinthe base sequence in C1 and D is selected from the group consisting ofbase sequences shown in SEQ ID NOs: 203 to 238, or wherein the basesequence in C2 is selected from the group consisting of base sequencesshown in SEQ ID NOs: 515 to
 535. 11. The method according to claim 10,wherein the comparison in D comprises selecting and combining any two ormore nucleic acid molecules comprising the allele and/or the genotype,comprising the high-risk allele, in the base sequences shown in SEQ IDNOs: 203 to 238, wherein the presence of a glaucoma risk is determinedin a case where the allele detected in C1 or C2 is a high-risk allele inany one of the nucleic acid molecules selected for the comparison in D,or wherein the presence of a glaucoma risk is determined in a case wherethe genotype detected in C1 or C2 is a homozygote or a heterozygote ofthe genotype in any one of the nucleic acid molecules selected for thecomparison in D when the high-risk allele complies with a dominantgenetic model, or wherein the presence of a glaucoma risk is determinedin a case where the genotype detected in C1 or C2 is a homozygote of thegenotype in any one of the nucleic acid molecules selected for thecomparison in D when the high-risk allele complies with a recessivegenetic model.
 12. The method according to claim 8, wherein thecomparison in D comprises selecting and combining all the nucleic acidmolecules comprising the alleles and/or the genotypes, comprising thehigh-risk allele, in the base sequences shown in SEQ ID NOs: 203 to 238,wherein the presence of a glaucoma risk is determined in a case wherethe allele detected in C1 or C2 is a high-risk allele in any one of thenucleic acid molecules selected for the comparison in D, or wherein thepresence of a glaucoma risk is determined in a case where the genotypedetected in C1 or C2 is a homozygote or a heterozygote of the genotypein any one of the nucleic acid molecules selected for the comparison inD when the high-risk allele complies with a dominant genetic model, orwherein the presence of a glaucoma risk is determined in a case wherethe genotype detected in C1 or C2 is a homozygote of the genotype in anyone of the nucleic acid molecules selected for the comparison in D whenthe high-risk allele complies with a recessive genetic model.
 13. Themethod according to claim 9, further comprising predicting the level ofthe onset risk.
 14. The method according to claim 8, wherein the nucleicacid molecule is used as a probe.
 15. The method according to claim 14,wherein the nucleic acid molecule is in the length of from 23 to 55bases.
 16. The method according to claim 14, wherein the probe isimmobilized.
 17. The method according to claim 8, wherein the glaucomais primary open-angle glaucoma (POAG) or normal tension glaucoma (NTG).18. A kit of determining the presence or the absence of a glaucoma risk,comprising a nucleic acid molecule comprising at least one base sequenceselected from the group consisting of base sequences shown in SEQ IDNOs: 203 to 514 or a complementary sequence thereto, or a partialsequence thereof, wherein the nucleic acid molecule comprises a singlenucleotide polymorphism which is located on a 31st base of a basesequence, and/or a nucleic acid molecule comprising a base sequencecomprising at least one base sequence selected from the group consistingof base sequences shown in SEQ ID NOs: 515 to 694 or a complementarysequence thereto, wherein the kit is for use in detecting in vitro anallele and/or a genotype of a single nucleotide polymorphism in a samplefrom a subject.
 19. The kit according to claim 18, wherein the glaucomarisk is an onset risk of glaucoma.
 20. The kit according to claim 19,wherein the base sequence is selected from the group consisting of basesequences shown in SEQ ID NOs: 203 to 238 and/or the group consisting ofSEQ ID NOs: 515 to
 535. 21. The kit according to claim 20, wherein thekit comprises any two or more nucleic acid molecules comprising a basesequence shown in SEQ ID NOs: 203 to 238 or a complementary sequencethereto, or a partial sequence thereof, and/or any two or more nucleicacid molecules comprising a base sequence shown in SEQ ID NOs: 515 to535 or a complementary sequence thereto.
 22. The kit according to claim21, wherein the kit comprises all of the nucleic acid moleculescomprising a base sequence shown in SEQ ID NOs: 203 to 238 or acomplementary sequence thereto, or a partial sequence thereof, and/orall of the nucleic acid molecules comprising a base sequence shown inSEQ ID NOs: 515 to 535 or a complementary sequence thereto.
 23. The kitaccording to claim 19, for use in further predicting the level of theonset risk.
 24. The kit according to claim 18, wherein the nucleic acidmolecule is used as a probe.
 25. The kit according to claim 24, whereinthe nucleic acid molecule is in the length of from 23 to 55 bases. 26.The kit according to claim 24, wherein the probe is immobilized.
 27. Thekit according to claim 18, wherein the glaucoma is primary open-angleglaucoma (POAG) or normal tension glaucoma (NTG).
 28. A method ofdetermining the presence or the absence of a glaucoma risk, comprising:(i): extracting a nucleic acid molecule from a sample from a subject,(ii): detecting an allele of a single nucleotide polymorphism which islocated on a 31st base of a base sequence, wherein the base sequence isat least one base sequence selected from base sequences shown in SEQ IDNOs: 203 to 514 or a complementary sequence thereto, for the nucleicacid molecule extracted in (i), and (iii): determining the presence orthe absence of a glaucoma risk, based on the allele detected in (ii).29. The method according to claim 28, wherein (iii) comprises ofdetermining a genotype, based on the allele detected in (ii).
 30. Themethod according to claim 28, wherein (iii) comprises the step ofdetermining whether or not the allele detected in (ii) is a high-riskallele.
 31. The method according to claim 30, wherein (iii) comprisesthe step of determining that the glaucoma risk is high in a case wherethe allele detected in (ii) is the high-risk allele.
 32. A nucleic acidmolecule for determining a glaucoma risk, wherein the nucleic acidmolecule comprises at least one base sequence, the base sequence being abase sequence selected from the group consisting of base sequences shownin SEQ ID NOs: 203 to 514 or a complementary sequence thereto, or apartial sequence thereof, wherein the nucleic acid molecule comprises anallele and/or a genotype of a single nucleotide polymorphism which islocated on a 31st base of a base sequence.
 33. A method of diagnosingglaucoma, comprising: E. detecting in vitro an allele and/or a genotypeof a single nucleotide polymorphism which is located on a 31st base of abase sequence, in a sample from a subject, wherein the base sequence isat least one base sequence selected from the group consisting of basesequences shown in SEQ ID NOs: 203 to 514 or a complementary sequencethereto, and F. comparing the allele and/or the genotype detected in Ewith at least one of an allele and/or a genotype, comprising a high-riskallele, in the base sequences shown in SEQ ID NOs: 203 to 514, whereinthe subject is diagnosed as glaucoma in a case where the allele detectedin E is the high-risk allele, or wherein the subject is diagnosed asglaucoma in a case where the genotype detected in E is a homozygote ofthe genotype comprising the high-risk allele or a heterozygote when thehigh-risk allele complies with a dominant genetic model, or wherein thesubject is diagnosed as glaucoma in a case where the genotype detectedin E is a homozygote of the genotype comprising the high-risk allelewhen the high-risk allele complies with a recessive genetic model.
 34. Amethod of determining an onset risk of glaucoma, comprising: (I):determining the presence or the absence of the onset risk of glaucoma,comprising, A. detecting in vitro an allele and/or a genotype of asingle nucleotide polymorphism which is located on a 31st base of a basesequence, in a sample from a subject, wherein the base sequence is atleast one base sequence selected from the group consisting of basesequences shown in SEQ ID NOs: 203 to 238 or a complementary sequencethereto, and B. comparing the allele and/or the genotype detected in Awith at least one of an allele and/or a genotype, comprising a high-riskallele, in the base sequences shown in SEQ ID NOs: 203 to 238, whereinthe presence of a glaucoma risk is determined in a case where the alleledetected in A is the high-risk allele, or wherein the presence of aglaucoma risk is determined in a case where the genotype detected in Ais a homozygote of the genotype comprising the high-risk allele or aheterozygote when the high-risk allele complies with a dominant geneticmodel, or wherein the presence of a glaucoma risk is determined in acase where the genotype detected in A is a homozygote of the genotypecomprising the high-risk allele when the high-risk allele complies witha recessive genetic model, (II): determining that a further riskdetermination is needed, in a case where the presence of the onset riskis determined in (I) for any one of single nucleotide polymorphisms, and(III): further determining the presence or the absence of the onset riskof glaucoma in a case of being determined that a further riskdetermination is needed in (II) by means of the method as defined inclaim 5.